Compounds and methods for treatment and diagnosis of mycobacterial infections

ABSTRACT

The present invention provides polypeptides comprising an immunogenic portion of a M. vaccae protein and DNA molecules encoding such polypeptides, together with methods for their use in the diagnosis and treatment of mycobacterial infection. Methods for enhancing the immune response to an antigen including administration of M. vaccae culture filtrate or delipidated M. vaccae cells are also provided.

REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 08/873,970, filed Jun. 12, 1997, which is acontinuation-in-part of U.S. patent application Ser. No. 08/705,347,filed Aug. 29, 1996.

TECHNICAL FIELD

The present invention relates generally to the detection, treatment andprevention of infectious diseases. In particular, the invention isrelated to compounds and methods for the treatment of mycobacterialinfections including Mycobacterium tuberculosis and Mycobacterium avium.The invention is further related to compounds that function asnon-specific immune response amplifiers, and the use of suchnon-specific immune response amplifiers as adjuvants in vaccination orimmunotherapy against infectious disease, and in certain treatments forimmune disorders and cancer.

BACKGROUND OF THE INVENTION

Tuberculosis is a chronic, infectious disease, that is caused byinfection with Mycobacterium tuberculosis (M. tuberculosis). It is amajor disease in developing countries, as well as an increasing problemin developed areas of the world, with about 8 million new cases and 3million deaths each year. Although the infection may be asymptomatic fora considerable period of time, the disease is most commonly manifestedas a chronic inflammation of the lungs, resulting in fever andrespiratory symptoms. If left untreated, significant morbidity and deathmay result.

Although tuberculosis can generally be controlled using extendedantibiotic therapy, such treatment is not sufficient to prevent thespread of the disease. Infected individuals may be asymptomatic, butcontagious, for some time. In addition, although compliance with thetreatment regimen is critical, patient behaviour is difficult tomonitor. Some patients do not complete the course of treatment, whichcan lead to ineffective treatment and the development of drug resistantmycobacteria.

Inhibiting the spread of tuberculosis requires effective vaccination andaccurate, early diagnosis of the disease. Currently, vaccination withlive bacteria is the most efficient method for inducing protectiveimmunity. The most common mycobacterium employed for this purpose isBacillus Calmette-Guerin (BCG), an avirulent strain of Mycobacteriumbovis. However, the safety and efficacy of BCG is a source ofcontroversy and some countries, such as the United States, do notvaccinate the general public. Diagnosis of M. tuberculosis infection iscommonly achieved using a skin test, which involves intradermal exposureto tuberculin PPD (protein-purified derivative). Antigen-specific T cellresponses result in measurable induration at the injection site by 48-72hours after injection, thereby indicating exposure to mycobacterialantigens. Sensitivity and specificity have, however, been a problem withthis test, and individuals vaccinated with BCG cannot be distinguishedfrom infected individuals.

A less well-known mycobacterium that has been used for immunotherapy fortuberculosis, and also leprosy, is Mycobacterium vaccae, which isnon-pathogenic in humans. However, there is less information on theefficacy of M. vaccae compared with BCG, and it has not been used widelyto vaccinate the general public. M. bovis BCG and M. vaccae are believedto contain antigenic compounds that are recognised by the immune systemof individuals exposed to infection with M. tuberculosis.

Several patents and other publications disclose treatment of variousconditions by administering mycobacteria, including M. vaccae, orcertain mycobacterial fractions. International Patent Publication WO91/02542 discloses treatment of chronic inflammatory disorders in whicha patient demonstrates an abnormally high release of IL-6 and/or TNF orin which the patient's IgG shows an abnormally high proportion ofagalactosyl IgG. Among the disorders mentioned in this publication arepsoriasis, rheumatoid arthritis, mycobacterial disease, Crohn's disease,primary biliary cirrhosis, sarcoidosis, ulcerative colitis, systemiclupus erythematosus, multiple sclerosis, Guillain-Barre syndrome,primary diabetes mellitus, and some aspects of graft rejection. Thetherapeutic agent preferably comprises autoclaved M. vaccae administeredby injection in a single dose.

U.S. Pat. No. 4,716,038 discloses diagnosis of, vaccination against andtreatment of autoimmune diseases of various types, including arthriticdiseases, by administering mycobacteria, including M. vaccae. U.S. Pat.No. 4,724,144 discloses an immunotherapeutic agent comprising antigenicmaterial derived from M. vaccae for treatment of mycobacterial diseases,especially tuberculosis and leprosy, and as an adjuvant to chemotherapy.International Patent Publication WO 91/01751 discloses the use ofantigenic and/or immunoregulatory material from M. vaccae as animmunoprophylactic to delay and/or prevent the onset of AIDS.International Patent Publication WO 94/06466 discloses the use ofantigenic and/or immunoregulatory material derived from M. vaccae fortherapy of HIV infection, with or without AIDS and with or withoutassociated tuberculosis.

U.S. Pat. No. 5,599,545 discloses the use of mycobacteria, especiallywhole, inactivated M. vaccae, as an adjuvant for administration withantigens which are not endogenous to M. vaccae. This publicationtheorises that the beneficial effect as an adjuvant may be due to heatshock protein 65 (hsp 65). International Patent Publication WO 92/08484discloses the use of antigenic and/or immunoregulatory material derivedfrom M. vaccae for the treatment of uveitis. International PatentPublication WO 93/16727 discloses the use of antigenic and/orimmunoregulatory material derived from M. vaccae for the treatment ofmental diseases associated with an autoimmune reaction initiated by aninfection. International Patent Publication WO 95/26742 discloses theuse of antigenic and/or immunoregulatory material derived from M. vaccaefor delaying or preventing the growth or spread of tumors.

There remains a need in the art for effective compounds and methods forpreventing, treating and detecting tuberculosis.

SUMMARY OF THE INVENTION

Briefly stated, the present invention provides compounds and methods forthe prevention, treatment and diagnosis of mycobacterial infection,together with adjuvants for use in vaccines or immunotherapy ofinfectious diseases and cancers.

In a first aspect, polypeptides derived from Mycobacterium vaccae areprovided comprising an immunogenic portion of an antigen, or a variantof such an antigen. In one embodiment, the antigen includes an aminoacid sequence selected from the group consisting of: (a) sequencesrecited in SEQ ID NOS: 70, 75, 89, 94, 100, 105, 109, 110, 112, 121,124, 125, 134, 135, 140, 141, 143, 145, 147, 152, 154 156, 158, 160,165, 166, 170, 172, 174, 177, 178, 181, 182, 184, 186, 187, 192 and 194;and (b) sequences having at least about a 99% probability of being thesame as a sequence recited in SEQ ID NOS: 70, 75, 89, 94, 100, 105, 109,110, 112, 121, 124, 125, 134, 135, 140, 141, 143, 145, 147, 152, 154156, 158, 160, 165, 166, 170, 172, 174, 177, 178, 181, 182, 184, 186,187, 192 and 194 as measured by the computer algorithm BLASTP.

In a second aspect, the invention provides polypeptides comprising animmunogenic portion of an M. vaccae antigen wherein the antigencomprises an amino acid sequence encoded by a DNA molecule selected fromthe group consisting of: (a) sequences recited in SEQ ID NOS: 74, 88,93, 97, 99, 106-108, 111, 120, 122, 123, 132, 133, 136-138, 142, 144,146, 151, 153, 155, 157, 159, 161, 162, 163, 164, 169, 171, 173, 175,176, 179, 180, 183, 185, 191 and 193; (b) complements of the sequencesrecited in SEQ ID NOS: 74, 88, 93, 97, 99, 106-108, 111, 120, 122, 123,132, 133, 136-138, 142, 144, 146, 151, 153, 155, 157, 159, 161, 162,163, 164, 169, 171, 173, 175, 176, 179, 180, 183, 185, 191 and 193; and(c) sequences having at least about a 99% probability of being the sameas a sequence of (a) or (b) as measured by the computer algorithm FASTA.

DNA sequences encoding the inventive polypeptides, expression vectorscomprising these DNA sequences, and host cells transformed ortransfected with such expression vectors are also provided.

In another aspect, the present invention provides fusion proteinscomprising a first and a second inventive polypeptide or, alternatively,an inventive polypeptide and a known M. tuberculosis antigen.

Within other aspects, the present invention provides pharmaceuticalcompositions that comprise at least one of the inventive polypeptides,or a DNA molecule encoding such a polypeptide, and a physiologicallyacceptable carrier. The invention also provides vaccines comprising atleast one of the above polypeptides and a non-specific immune responseamplifier, together with vaccines comprising at least one DNA sequenceencoding such polypeptides and a non-specific immune response amplifier.

In yet another aspect, methods are provided for inducing protectiveimmunity in a patient, comprising administering to a patient aneffective amount of one or more of the above polypeptides together withan immune response amplifier.

In further aspects of this invention, methods and diagnostic kits areprovided for detecting tuberculosis in a patient. In a first embodiment,the method comprises contacting dermal cells of a patient with one ormore of the above polypeptides and detecting an immune response on thepatient's skin. In a second embodiment, the method comprises contactinga biological sample with at least one of the above polypeptides; anddetecting in the sample the presence of antibodies that bind to thepolypeptide or polypeptides, thereby detecting M. tuberculosis infectionin the biological sample. Suitable biological samples include wholeblood, sputum, serum, plasma, saliva, cerebrospinal fluid and urine.

Diagnostic kits comprising one or more of the above polypeptides incombination with an apparatus sufficient to contact the polypeptide withthe dermal cells of a patient are provided. The present invention alsoprovides diagnostic kits comprising one or more of the inventivepolypeptides in combination with a detection reagent.

In yet another aspect, the present invention provides antibodies, bothpolyclonal and monoclonal, that bind to the polypeptides describedabove, as well as methods for their use in the detection of M.tuberculosis infection.

The present invention also provides methods for enhancing a non-specificimmune response to an antigen. In one embodiment, such methods compriseadministering a composition comprising a component selected from thegroup consisting of: (a) delipidated M. vaccae cells, (b)deglycolipidated M. vaccae cells; (c) delipidated and deglycolipidatedM. vaccae cells and (d) M. vaccae culture filtrate. In a secondembodiment, such methods comprise administering a polypeptide, thepolypeptide comprising an immunogenic portion of an antigen, whereinsaid antigen includes a sequence selected from the group consisting of:(a) sequences recited in SEQ ID NOS: **114, 117 and 118; and (b)sequences having at least about 97% identity to a sequence recited inSEQ ID NOS: **114, 117 and 118.

In yet a further aspect, compositions comprising a component selectedfrom the group consisting of delipidated M. vaccae cells,deglycolipidated M. vaccae cells, and delipidated and deglycolipidatedM. vaccae cells are provided, together with vaccines comprising suchcomponents and methods of using such compositions and vaccines to induceprotective immunity in a patient.

These and other aspects of the present invention will become apparentupon reference to the following detailed description and attacheddrawings. All references disclosed herein are hereby incorporated byreference in their entirety as if each was incorporated individually.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A and 1B illustrate the protective effects of immunizing micewith autoclaved M. vaccae or unfractionated M. vaccae culture filtrates,respectively, prior to infection with live M. tuberculosis H37Rv.

FIGS. 2A and B show components of M. vaccae and M. tuberculosis culturefiltrates, respectively, as analysed by 2-dimensional polyacrylamide gelelectrophoresis.

FIG. 3 is a comparison of the Antigen 85A protein sequence obtained fromM. vaccae with those from M. bovis, M. tuberculosis and M. leprae.

FIG. 4A(i)-(iv) illustrate the non-specific immune amplifying effects of10 μg, 100 μg and 1 mg autoclaved M. vaccae and 75 μg unfractionatedculture filtrates of M. vaccae, respectively.

FIG. 4B(i) and (ii) illustrate the non-specific immune amplifyingeffects of autoclaved M. vaccae, and delipidated and deglycolipidated M.vaccae, respectively. FIG. 4C(i) illustrates the non-specific immuneamplifying effects of whole autoclaved M. vaccae.

FIG. 4C(ii) illustrates the non-specific immune amplifying effectsofsoluble M. vaccae proteins extracted with SDS from delipidated anddeglycolipidated M. vaccae.

FIG. 4C(iii) illustrates that the non-specific amplifying effects of thepreparation of FIG. 4C(ii) are destroyed by treatment with theproteolytic enzyme Pronase.

FIG. 4D illustrates the non-specific immune amplifying effects ofheat-killed M. vaccae (FIG. 4D(i)),whereas a non-specific immuneamplifying effect was not seen with heat-killed preparations of M.tuberculosis (FIG. 4D(ii)), M. bovis BCG (FIG. 4D(iii)), M. phlei (FIG.4D(iv)) and M. smegmatis (FIG. 4D(v)).

FIG. 5 shows the results of polyacrylamide gel electrophoresis analysisof SDS-extracted proteins derived from delipidated and deglycolipidatedM. vaccae.

FIG. 6 illustrates the non-specific immune amplifying effects ofdifferent molecular weight fractions of SDS-extracted M. vaccaeproteins.

FIG. 7 illustrates the non-specific immune amplifying effects ofdifferent pI fractions of SDS-extracted M. vaccae proteins.

FIG. 8 illustrates the induction of IL-12 by autoclaved M. vaccae ,lyophilized M. vaccae, delipidated and deglycolipidated M. vaccae and M.vaccae glycolipids.

FIGS. 9A, B and C illustrate the stimulation of interferon-gammaproduction by different concentrations of M. vaccae recombinantproteins, heat-killed M. vaccae, delipidated and deglycolipidated M.vaccae (referred to in the figure as "delipidated M. vaccae"), M. vaccaeglycolipids and lipopolysaccharide, in peritoneal macrophages fromC57BL/6 mice (FIG. 9A), BALB/C mice (FIG. 9B) or C3H/HeJ mice (FIG. 9C).

FIG. 10 compares the in vitro stimulation of interferon-gamma productionin spleen cells from Severe Combined ImmunoDeficient (SCID) mice bydifferent concentrations of heat-killed (autoclaved) M. vaccae,delipidated and deglycolipidated M. vaccae, and M. vaccae glycolipids.

DETAILED DESCRIPTION OF THE INVENTION

As noted above, the present invention is generally directed tocompositions and methods for preventing, treating and diagnosingmycobacterial infections, including M. tuberculosis and M. aviuminfections.

Considerable research efforts have been directed towards elucidating themechanism of immune response to mycobacterial infection, in particularM. tuberculosis infection. While macrophages have been shown to act asthe principal effectors of M. tuberculosis immunity, T cells are thepredominant inducers of such immunity. The essential role of T cells inprotection against M. tuberculosis infection is illustrated by thefrequent occurrence of M. tuberculosis in AIDS patients, due to thedepletion of CD4 T cells associated with human immunodeficiency virus(HIV) infection. Mycobacterium-reactive CD4 T cells have been shown tobe potent producers of gamma-interferon (IFN-γ), which, in turn, hasbeen shown to trigger the anti-mycobacterial effects of macrophages inmice. While the role of IFN-γ in humans is less clear, studies haveshown that 1,25-dihydroxy-vitamin D3, either alone or in combinationwith IFN-γ or tumor necrosis factor-alpha, activates human macrophagesto inhibit M. tuberculosis infection. Furthermore, it is known thatIFN-γ stimulates human macrophages to make 1,25-dihydroxy-vitamin D3.Similarly, IL-12 has been shown to play a role in stimulating resistanceto M. tuberculosis infection. Another property of CD4⁺ T cells andmacrophages is their ability to activate CD8⁺ cytotoxic T cells whichare capable of killing pathogen-infected cells. CD8⁺ T cells have beenshown to kill macrophages and other cells that harbour M. tuberculosis.For a review of the immunology of M. tuberculosis infection see Chan andKaufmann in Tuberculosis: Pathogenesis, Protection and Control, Bloom(ed.), ASM Press, Washington, DC, 1994.

The compositions of the present invention include polypeptides thatcomprise at least one immunogenic portion of aM. vaccae antigen, or avariant thereof. Such polypeptides stimulate T cell proliferation,and/or, interferon gamma secretion from T cells of individuals exposedto M. tuberculosis. In certain embodiments, the inventive polypeptidescomprise at least an immunogenic portion of a soluble M. vaccae antigen.A "soluble M. vaccae antigen" is a protein of M. vaccae origin that ispresent in M. vaccae culture filtrate. As used herein, the term"polypeptide" encompasses amino acid chains of any length, includingfull length proteins (i.e., antigens), wherein the amino acid residuesare linked by covalent peptide bonds. Thus, a polypeptide comprising animmunogenic portion of one of the above antigens may consist entirely ofthe immunogenic portion, or may contain additional sequences. Theadditional sequences may be derived from the native M. vaccae antigen ormay be heterologous, and such sequences may (but need not) beimmunogenic.

"Immunogenic," as used herein, refers to the ability to elicit an immuneresponse in a patient, such as a human, or in a biological sample. Inparticular, immunogenic antigens are capable of stimulating cellproliferation, interleukin-12 production or interferon-γ production inbiological samples comprising one or more cells selected from the groupof T cells, NK cells, B cells and macrophages, where the cells arederived from an M. tuberculosis-immune individual. Polypeptidescomprising at least an immunogenic portion of one or more M. vaccaeantigens may generally be used to detect tuberculosis or to induceprotective immunity against tuberculosis in a patient.

The compositions and methods of this invention also encompass variantsof the above polypeptides. As used herein, the term "variant" covers anysequence which exhibits at least about 50%, more preferably at leastabout 70% and more preferably yet, at least about 90% identity to asequence of the present invention. Most preferably, a "variant" is anysequence which has at least about a 99% probability of being the same asthe inventive sequence. The probability for DNA sequences is measured bythe computer algorithm FASTA (version 2.0u4, February 1996; Pearson W.R. et al., Proc. Natl. Acad. Sci., 85:2444-2448, 1988), the probabilityfor translated DNA sequences is measured by the computer algorithmTBLASTX and that for protein sequences is measured by the computeralgorithm BLASTP (Altschul, S. F. et al. J. Mol. Biol., 215:403-410,1990). The term "variants" thus encompasses sequences wherein theprobability of finding a match by chance (smallest sum probability), isless than about 1% as measured by any of the above tests.

A polypeptide of the present invention may be conjugated to a signal (orleader) sequence at the N-terminal end of the protein whichco-translationally or post-translationally directs transfer of theprotein. The polypeptide may also be conjugated to a linker or othersequence for ease of synthesis, purification or identification of thepolypeptide (e.g., poly-His), or to enhance binding of the polypeptideto a solid support. For example, a polypeptide may be conjugated to animmunoglobulin Fc region.

In general, M. vaccae antigens, and DNA sequences encoding suchantigens, may be prepared using any of a variety of procedures. Forexample, soluble antigens may be isolated from M. vaccae culturefiltrate as described below. Antigens may also be produced recombinantlyby inserting a DNA sequence that encodes the antigen into an expressionvector and expressing the antigen in an appropriate host. Any of avariety of expression vectors known to those of ordinary skill in theart may be employed. Expression may be achieved in any appropriate hostcell that has been transformed or transfected with an expression vectorcontaining a DNA molecule that encodes a recombinant polypeptide.Suitable host cells include prokaryotes, yeast and higher eukaryoticcells. Preferably, the host cells employed are E. coli, mycobacteria,insect, yeast or a mammalian cell line such as COS or CHO. The DNAsequences expressed in this manner may encode naturally occurringantigens, portions of naturally occurring antigens, or other variantsthereof.

DNA sequences encoding M. vaccae antigens may be obtained by screeningan appropriate M. vaccae cDNA or genomic DNA library for DNA sequencesthat hybridize to degenerate oligonucleotides derived from partial aminoacid sequences of isolated soluble antigens. Suitable degenerateoligonucleotides may be designed and synthesized, and the screen may beperformed as described, for example in Maniatis et al., MolecularCloning: A Laboratory Manual, Cold Spring Harbor Laboratories, ColdSpring Harbor, N.Y., 1989. As described below, polymerase chain reaction(PCR) may be employed to isolate a nucleic acid probe from genomic DNA,or a cDNA or genomic DNA library. The library screen may then beperformed using the isolated probe.

DNA molecules encoding M. vaccae antigens may also be isolated byscreening an appropriate M. vaccae expression library with anti-sera(e.g., rabbit or monkey) raised specifically against M. vaccae antigens.

Regardless of the method of preparation, the antigens described hereinhave the ability to induce an immunogenic response. More specifically,the antigens have the ability to induce cell proliferation and/orcytokine production (for example, interferon-γ and/or interleukin-12production) in T cells, NK cells, B cells or macrophages derived from anM. tuberculosis-immune individual. An M. tuberculosis-immune individualis one who is considered to be resistant to the development oftuberculosis by virtue of having mounted an effective T cell response toM. tuberculosis. Such individuals may be identified based on a stronglypositive (i.e., greater than about 10 mm diameter induration)intradermal skin test response to tuberculosis proteins (PPD), and anabsence of any symptoms of tuberculosis infection.

The selection of cell type for use in evaluating an immunogenic responseto an antigen will depend on the desired response. For example,interleukin-12 production is most readily evaluated using preparationscontaining T cells, NK cells, B cells and macrophages derived from M.tuberculosis-immune individuals may be prepared using methods well knownin the art. For example, a preparation of peripheral blood mononuclearcells (PBMCs) may be employed without further separation of componentcells. PBMCs may be prepared, for example, using density centrifugationthrough Ficoll™ (Winthrop Laboratories, NY). T cells for use in theassays described herein may be purified directly from PBMCs.Alternatively, an enriched T cell line reactive against mycobacterialproteins, or T cell clones reactive to individual mycobacterialproteins, may be employed. Such T cell clones may be generated by, forexample, culturing PBMCs from M. tuberculosis-immune individuals withmycobacterial proteins for a period of 2-4 weeks. This allows expansionof only the mycobacterial protein-specific T cells, resulting in a linecomposed solely of such cells. These cells may then be cloned and testedwith individual proteins, using methods well known in the art, to moreaccurately define individual T cell specificity. Assays for cellproliferation or cytokine production in T cells, NK cells, B cells ormacrophages may be performed, for example, using the proceduresdescribed below.

In general, immunogenic antigens are those antigens that stimulateproliferation or cytokine production (i.e., interferon-γ and/orinterleukin-12 production) in T cells, NK cells, B cells or macrophagesderived from at least about 25% of M. tuberculosis-immune individuals.Among these immunogenic antigens, polypeptides having superiortherapeutic properties may be distinguished based on the magnitude ofthe responses in the above assays and based on the percentage ofindividuals for which a response is observed. In addition, antigenshaving superior therapeutic properties will not stimulate cellproliferation or cytokine production in vitro in cells derived from morethan about 25% of individuals that are not M. tuberculosis-immune,thereby eliminating responses that are not specifically due to M.tuberculosis-responsive cells. Thus, those antigens that induce aresponse in a high percentage of T cell, NK cell, B cell or macrophagepreparations from M. tuberculosis-immune individuals (with a lowincidence of responses in cell preparations from other individuals) havesuperior therapeutic properties.

Antigens with superior therapeutic properties may also be identifiedbased on their ability to diminish the severity of M. tuberculosisinfection, or other mycobacterial infection, in experimental animals,when administered as a vaccine. Suitable vaccine preparations for use inexperimental animals are described in detail below.

Antigens having superior diagnostic properties may generally beidentified based on the ability to elicit a response in an intradermalskin test performed on an individual with active tuberculosis, but notin a test performed on an individual who is not infected with M.tuberculosis. Skin tests may generally be performed as described below,with a response of at least about 5 mm induration considered positive.

Immunogenic portions of the antigens described herein may be preparedand identified using well known techniques, such as those summarized inPaul, Fundamental Immunology, 3d ed., Raven Press, 1993, pp. 243-247.Such techniques include screening polypeptide portions of the nativeantigen for immunogenic properties. The representative proliferation andcytokine production assays described herein may be employed in thesescreens. An immunogenic portion of a polypeptide is a portion that,within such representative assays, generates an immune response (e.g.,cell proliferation, interferon-γ production or interleukin-12production) that is substantially similar to that generated by thefull-length antigen. In other words, an immunogenic portion of anantigen may generate at least about 20%, preferably about 65%, and mostpreferably about 100%, of the proliferation induced by the full-lengthantigen in the model proliferation assay described herein. Animmunogenic portion may also, or alternatively, stimulate the productionof at least about 20%, preferably about 65% and most preferably about100%, of the interferon-γ and/or interleukin-12 induced by the fulllength antigen in the model assay described herein.

Portions and other variants of M. vaccae antigens may be generated bysynthetic or recombinant means. Synthetic polypeptides having fewer thanabout 100 amino acids, and generally fewer than about 50 amino acids,may be generated using techniques well known to those of ordinary skillin the art. For example, such polypeptides may be synthesized using anyof the commercially available solid-phase techniques, such as theMerrifield solid-phase synthesis method, where amino acids aresequentially added to a growing amino acid chain. See Merrifield, J. Am.Chem. Soc. 85:2149-2146, 1963. Equipment for automated synthesis ofpolypeptides is commercially available from suppliers such as PerkinElmer/Applied BioSystems, Inc. (Foster City, Calif.), and may beoperated according to the manufacturer's instructions. Variants of anative antigen may be prepared using standard mutagenesis techniques,such as oligonucleotide-directed site-specific mutagenesis. Sections ofthe DNA sequence may also be removed using standard techniques to permitpreparation of truncated polypeptides.

In general, regardless of the method of preparation, the polypeptidesdisclosed herein are prepared in substantially pure form. Preferably,the polypeptides are at least about 80% pure, more preferably at leastabout 90% pure and most preferably at least about 99% pure. In certainpreferred embodiments, described in detail below, the substantially purepolypeptides are incorporated into pharmaceutical compositions orvaccines for use in one or more of the methods disclosed herein.

The present invention also provides fusion proteins comprising a firstand a second inventive polypeptide or, alternatively, a polypeptide ofthe present invention and a known M. tuberculosis antigen, such as the38 kDa antigen described in Andersen and Hansen, Infect. Immun.57:2481-2488, 1989, together with variants of such fusion proteins. Thefusion proteins of the present invention may also include a linkerpeptide between the first and second polypeptides.

A DNA sequence encoding a fusion protein of the present invention isconstructed using known recombinant DNA techniques to assemble separateDNA sequences encoding the first and second polypeptides into anappropriate expression vector. The 3' end of a DNA sequence encoding thefirst polypeptide is ligated, with or without a peptide linker, to the5' end of a DNA sequence encoding the second polypeptide so that thereading frames of the sequences are in phase to permit mRNA translationof the two DNA sequences into a single fusion protein that retains thebiological activity of both the first and the second polypeptides.

A peptide linker sequence may be employed to separate the first and thesecond polypeptides by a distance sufficient to ensure that eachpolypeptide folds into its secondary and tertiary structures. Such apeptide linker sequence is incorporated into the fusion protein usingstandard techniques well known in the art. Suitable peptide linkersequences may be chosen based on the following factors: (1) theirability to adopt a flexible extended conformation; (2) their inabilityto adopt a secondary structure that could interact with functionalepitopes on the first and second polypeptides; and (3) the lack ofhydrophobic or charged residues that might react with the polypeptidefunctional epitopes. Preferred peptide linker sequences contain Gly, Asnand Ser residues. Other near neutral amino acids, such as Thr and Alamay also be used in the linker sequence. Amino acid sequences which maybe usefully employed as linkers include those disclosed in Maratea etal., Gene 40:39-46, 1985; Murphy et al., Proc. Natl. Acad. Sci USA83:8258-8262, 1986; U.S. Pat. No. 4,935,233 and U.S. Pat. No. 4,751,180.The linker sequence may be from 1 to about 50 amino acids in length.Peptide linker sequences are not required when the first and secondpolypeptides have non-essential N-terminal amino acid regions that canbe used to separate the functional domains and prevent stericinterference.

The ligated DNA sequences encoding the fusion proteins are cloned intosuitable expression systems using techniques known to those of ordinaryskill in the art.

In another aspect, the present invention provides methods for using oneor more of the inventive polypeptides or fusion proteins (or DNAmolecules encoding such polypeptides or fusion proteins) to induceprotective immunity against tuberculosis in a patient. As used herein, a"patient" refers to any warm-blooded animal, preferably a human. Apatient may be afflicted with a disease, or may be free of detectabledisease or infection. In other words, protective immunity may be inducedto prevent or treat tuberculosis.

In this aspect, the polypeptide, fusion protein or DNA molecule isgenerally present within a pharmaceutical composition or a vaccine.Pharmaceutical compositions may comprise one or more polypeptides, eachof which may contain one or more of the above sequences (or variantsthereof, and a physiologically acceptable carrier. Vaccines may compriseone or more of the above polypeptides and a non-specific immune responseamplifier, such as an adjuvant or a liposome, into which the polypeptideis incorporated. Such pharmaceutical compositions and vaccines may alsocontain other mycobacterial antigens, either, as discussed above,incorporated into a fusion protein or present within a separatepolypeptide.

Alternatively, a vaccine of the present invention may contain DNAencoding one or more polypeptides as described above, such that thepolypeptide is generated in situ. In such vaccines, the DNA may bepresent within any of a variety of delivery systems known to those ofordinary skill in the art, including nucleic acid expression systems,bacterial and viral expression systems. Appropriate nucleic acidexpression systems contain the necessary DNA sequences for expression inthe patient (such as a suitable promoter and terminator signal).Bacterial delivery systems involve the administration of a bacterium(such as Bacillus-Calmette-Guerin) that expresses an immunogenic portionof the polypeptide on its cell surface. In a preferred embodiment, theDNA may be introduced using a viral expression system (e.g., vaccinia orother poxvirus, retrovirus, or adenovirus), which may involve the use ofa non-pathogenic, or defective, replication competent virus. Techniquesfor incorporating DNA into such expression systems are well known in theart. The DNA may also be "naked," as described, for example, in Ulmer etal., Science 259:1745-1749, 1993 and reviewed by Cohen, Science259:1691-1692, 1993. The uptake of naked DNA may be increased by coatingthe DNA onto biodegradable beads, which are efficiently transported intothe cells.

A DNA vaccine as described above may be administered simultaneously withor sequentially to either a polypeptide of the present invention or aknown mycobacterial antigen, such as the 38 kDa antigen described above.For example, administration of DNA encoding a polypeptide of the presentinvention, may be followed by administration of an antigen in order toenhance the protective immune effect of the vaccine.

Routes and frequency of administration, as well as dosage, will varyfrom individual to individual and may parallel those currently beingused in immunization using BCG. In general, the pharmaceuticalcompositions and vaccines may be administered by injection (e.g.,intradermal, intramuscular, intravenous or subcutaneous), intranasally(e.g., by aspiration) or orally. Between 1 and 3 doses may beadministered for a 1-36 week period. Preferably, 3 doses areadministered, at intervals of 3-4 months, and booster vaccinations maybe given periodically thereafter. Alternate protocols may be appropriatefor individual patients. A suitable dose is an amount of polypeptide orDNA that, when administered as described above, is capable of raising animmune response in a patient sufficient to protect the patient frommycobacterial infection for at least 1-2 years. In general, the amountof polypeptide present in a dose (or produced in situ by the DNA in adose) ranges from about 1 pg to about 100 mg per kg of host, typicallyfrom about 10 pg to about 1 mg, and preferably from about 100 pg toabout 1 μg. Suitable dose sizes will vary with the size of the patient,but will typically range from about 0.1 ml to about 5 ml.

While any suitable carrier known to those of ordinary skill in the artmay be employed in the pharmaceutical compositions of this invention,the type of carrier will vary depending on the mode of administration.For parenteral administration, such as subcutaneous injection, thecarrier preferably comprises water, saline, alcohol, a fat, a wax or abuffer. For oral administration, any of the above carriers or a solidcarrier, such as mannitol, lactose, starch, magnesium stearate, sodiumsaccharine, talcum, cellulose, glucose, sucrose, and magnesiumcarbonate, may be employed. Biodegradable microspheres (e.g., polylacticgalactide) may also be employed as carriers for the pharmaceuticalcompositions of this invention. Suitable biodegradable microspheres aredisclosed, for example, in U.S. Pat. Nos. 4,897,268 and 5,075,109.

Any of a variety of adjuvants may be employed in the vaccines of thisinvention to non-specifically enhance the immune response. Mostadjuvants contain a substance designed to protect the antigen from rapidcatabolism, such as aluminum hydroxide or mineral oil, and anon-specific stimulator of immune responses, such as lipid A, Bordetellapertussis, M. tuberculosis, or, as discussed below, M. vaccae. Suitableadjuvants are commercially available as, for example, Freund'sIncomplete Adjuvant and Freund's Complete Adjuvant (Difco Laboratories,Detroit, Mich.), and Merck Adjuvant 65 (Merck and Company, Inc., Rahway,N.J.). Other suitable adjuvants include alum, biodegradablemicrospheres, monophosphoryl lipid A and Quil A.

In another aspect, this invention provides methods for using one or moreof the polypeptides described above to diagnose tuberculosis using askin test. As used herein, a "skin test" is any assay performed directlyon a patient in which a delayed-type hypersensitivity (DTH) reaction(such as swelling, reddening or dermatitis) is measured followingintradermal injection of one or more polypeptides as described above.Preferably, the reaction is measured at least 48 hours after injection,more preferably 48-72 hours.

The DTH reaction is a cell-mediated immune response, which is greater inpatients that have been exposed previously to the test antigen (i.e.,the immunogenic portion of the polypeptide employed, or a variantthereof). The response may be measured visually, using a ruler. Ingeneral, a response that is greater than about 0.5 cm in diameter,preferably greater than about 1.0 cm in diameter, is a positiveresponse, indicative of tuberculosis infection.

For use in a skin test, the polypeptides of the present invention arepreferably formulated, as pharmaceutical compositions containing apolypeptide and a physiologically acceptable carrier, as describedabove. Such compositions typically contain one or more of the abovepolypeptides in an amount ranging from about 1 μg to about 100 μg,preferably from about 10 μg to about 50 μg in a volume of 0.1 ml.Preferably, the carrier employed in such pharmaceutical compositions isa saline solution with appropriate preservatives, such as phenol and/orTween 80™.

In a preferred embodiment, a polypeptide employed in a skin test is ofsufficient size such that it remains at the site of injection for theduration of the reaction period. In general, a polypeptide that is atleast 9 amino acids in length is sufficient. The polypeptide is alsopreferably broken down by macrophages or dendritic cells within hours ofinjection to allow presentation to T-cells. Such polypeptides maycontain repeats of one or more of the above sequences or otherimmunogenic or nonimmunogenic sequences.

In another aspect, methods are provided for detecting mycobacterialinfection in a biological sample, using one or more of the abovepolypeptides, either alone or in combination. In embodiments in whichmultiple polypeptides are employed, polypeptides other than thosespecifically described herein, such as the 38 kDa antigen describedabove, may be included. As used herein, a "biological sample" is anyantibody-containing sample obtained from a patient. Preferably, thesample is whole blood, sputum, serum, plasma, saliva, cerebrospinalfluid or urine. More preferably, the sample is a blood, serum or plasmasample obtained from a patient or a blood supply. The polypeptide(s) areused in an assay, as described below, to determine the presence orabsence of antibodies to the polypeptide(s) in the sample, relative to apredetermined cut-off value. The presence of such antibodies indicatesthe presence of mycobacterial infection.

In embodiments in which more than one polypeptide is employed, thepolypeptides used are preferably complementary (i.e., one componentpolypeptide will tend to detect infection in samples where the infectionwould not be detected by another component polypeptide). Complementarypolypeptides may generally be identified by using each polypeptideindividually to evaluate serum samples obtained from a series ofpatients known to be infected with a Mycobacterium. After determiningwhich samples test positive (as described below) with each polypeptide,combinations of two or more polypeptides may be formulated that arecapable of detecting infection in most, or all, of the samples tested.For example, approximately 25-30% of sera from tuberculosis-infectedindividuals are negative for antibodies to any single protein, such asthe 38 kDa antigen mentioned above. Complementary polypeptides may,therefore, be used in combination with the 38 kDa antigen to improvesensitivity of a diagnostic test.

A variety of assay formats employing one or more polypeptides to detectantibodies in a sample are well known in the art. See, e.g., Harlow andLane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory,1988. In a preferred embodiment, the assay involves the use ofpolypeptide immobilized on a solid support to bind to and remove theantibody from the sample. The bound antibody may then be detected usinga detection reagent that contains a reporter group. Suitable detectionreagents include antibodies that bind to the antibody/polypeptidecomplex and free polypeptide labelled with a reporter group (e.g., in asemi-competitive assay). Alternatively, a competitive assay may beutilized, in which an antibody that binds to the polypeptide is labelledwith a reporter group and allowed to bind to the immobilized antigenafter incubation of the antigen with the sample. The extent to whichcomponents of the sample inhibit the binding of the labelled antibody tothe polypeptide is indicative of the reactivity of the sample with theimmobilized polypeptide.

The solid support may be any solid material to which the antigen may beattached. Suitable materials are well known in the art. For example, thesolid support may be a test well in a microtiter plate or anitrocellulose or other suitable membrane. Alternatively, the supportmay be a bead or disc, such as glass, fiberglass, latex or a plasticmaterial such as polystyrene or polyvinylchloride. The support may alsobe a magnetic particle or a fiber optic sensor, such as those disclosed,for example, in U.S. Pat. No. 5,359,681.

The polypeptides may be bound to the solid support using a variety oftechniques well known in the art. In the context of the presentinvention, the term "bound" refers to both noncovalent association, suchas adsorption, and covalent attachment, which may be a direct linkagebetween the antigen and functional groups on the support or a linkage byway of a cross-linking agent. Binding by adsorption to a well in amicrotiter plate or to a membrane is preferred. In such cases,adsorption may be achieved by contacting the polypeptide, in a suitablebuffer, with the solid support for a suitable amount of time. Thecontact time varies with temperature, but is typically between about 1hour and 1 day. In general, contacting a well of a plastic microtiterplate (such as polystyrene or polyvinylchloride) with an amount ofpolypeptide ranging from about 10 ng to about 1 μg, and preferably about100 ng, is sufficient to bind an adequate amount of antigen.

Covalent attachment of polypeptide to a solid support may generally beachieved by first reacting the support with a bifunctional reagent thatwill react with both the support and a functional group, such as ahydroxyl or amino group, on the polypeptide. For example, thepolypeptide may be bound to supports having an appropriate polymercoating using benzoquinone or by condensation of an aldehyde group onthe support with an amine and an active hydrogen on the polypeptide(see, e.g., Pierce Immunotechnology Catalog and Handbook, 1991, atA12-A13).

In certain embodiments, the assay is an enzyme-linked immunosorbentassay (ELISA). This assay may be performed by first contacting apolypeptide antigen that has been immobilized on a solid support, withthe sample, such that antibodies to the polypeptide within the sampleare allowed to bind to the immobilized polypeptide. Unbound sample isthen removed from the immobilized polypeptide and a detection reagentcapable of binding to the immobilized antibody-polypeptide complex isadded. The amount of detection reagent that remains bound to the solidsupport is then determined using a method appropriate for the specificdetection reagent.

More specifically, once the polypeptide is immobilized on the support asdescribed above, the remaining protein binding sites on the support aretypically blocked. Any suitable blocking agent known to those ofordinary skill in the art, such as bovine serum albumin or Tween 20™(Sigma Chemical Co., St. Louis, Mo.) may be employed. The immobilizedpolypeptide is then incubated with the sample, and antibody is allowedto bind to the antigen. The sample may be diluted with a suitablediluent, such as phosphate-buffered saline (PBS) prior to incubation. Ingeneral, an appropriate contact time, or incubation time, is that periodof time that is sufficient to detect the presence of antibody within aM. tuberculosis-infected sample. Preferably, the contact time issufficient to achieve a level of binding that is at least 95% of thatachieved at equilibrium between bound and unbound antibody. The timenecessary to achieve equilibrium may be readily determined by assayingthe level of binding that occurs over a period of time. At roomtemperature, an incubation time of about 30 minutes is generallysufficient.

Unbound sample may be removed by washing the solid support with anappropriate buffer, such as PBS containing 0.1% Tween 20™. Detectionreagent may then be added to the solid support. An appropriate detectionreagent is any compound that binds to the immobilizedantibody-polypeptide complex and that can be detected by any of avariety of means known in the art. Preferably, the detection reagentcontains a binding agent (such as, for example, Protein A, Protein G,immunoglobulin, lectin or free antigen) conjugated to a reporter group.Preferred reporter groups include enzymes (such as horseradishperoxidase), substrates, cofactors, inhibitors, dyes, radionuclides,luminescent groups, fluorescent groups and biotin. The conjugation ofbinding agent to reporter group may be achieved using standard methodsknown in the art. Common binding agents may also be purchased conjugatedto a variety of reporter groups from many commercial sources (e.g.,Zymed Laboratories, San Francisco, Calif., and Pierce, Rockford, Ill.).

The detection reagent is incubated with the immobilizedantibody-polypeptide complex for an amount of time sufficient to detectthe bound antibody. An appropriate amount of time may generally bedetermined from the manufacturer's instructions or by assaying the levelof binding that occurs over a period of time. Unbound detection reagentis then removed and bound detection reagent is detected using thereporter group. The method employed for detecting the reporter groupdepends upon the nature of the reporter group. For radioactive groups,scintillation counting or autoradiographic methods are generallyappropriate. Spectroscopic methods may be used to detect dyes,luminescent groups and fluorescent groups. Biotin may be detected usingavidin, coupled to a different reporter group (commonly a radioactive orfluorescent group or an enzyme). Enzyme reporter groups may be detectedby the addition of substrate (generally for a specific period of time),followed by spectroscopic or other analysis of the reaction products.

To determine the presence or absence of anti-mycobacterial antibodies inthe sample, the signal detected from the reporter group that remainsbound to the solid support is generally compared to a signal thatcorresponds to a predetermined cut-off value. In one preferredembodiment, the cut-off value is the average mean signal obtained whenthe immobilized antigen is incubated with samples from an uninfectedpatient. In an alternate preferred embodiment, the cut-off value isdetermined using a Receiver Operator Curve, according to the method ofSackett et al., Clinical Epidemiology: A Basic Science for ClinicalMedicine, Little Brown and Co., 1985, pp. 106-107. In general, signalshigher than the predetermined cut-off value are considered to bepositive for mycobacterial infection.

The assay may also be performed in a rapid flow-through or strip testformat, wherein the antigen is immobilized on a membrane, such asnitrocellulose. In the flow-through test, antibodies within the samplebind to the immobilized polypeptide as the sample passes through themembrane. A detection reagent (e.g., protein A-colloidal gold) thenbinds to the antibody-polypeptide complex as the solution containing thedetection reagent flows through the membrane. The detection of bounddetection reagent may then be performed as described above. In the striptest format, one end of the membrane to which polypeptide is bound isimmersed in a solution containing the sample. The sample migrates alongthe membrane through a region containing detection reagent and to thearea of immobilized polypeptide. Concentration of detection reagent atthe polypeptide indicates the presence of anti-mycobacterial antibodiesin the sample. Typically, the concentration of detection reagent at thatsite generates a pattern, such as a line, that can be read visually. Theabsence of such a pattern indicates a negative result. In general, theamount of polypeptide immobilized on the membrane is selected togenerate a visually discernible pattern when the biological samplecontains a level of antibodies that would be sufficient to generate apositive signal in an ELISA, as discussed above. Preferably, the amountof polypeptide immobilized on the membrane ranges from about 25 ng toabout 1 μg, and more preferably from about 50 ng to about 500 ng. Suchtests can typically be performed with a very small amount (e.g., onedrop) of patient serum or blood.

Numerous other assay protocols exist that are suitable for use with thepolypeptides of the present invention. The above descriptions areintended to be exemplary only.

The present invention also provides antibodies to the inventivepolypeptides. Antibodies may be prepared by any of a variety oftechniques known to those of ordinary skill in the art. See, e.g.,Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring HarborLaboratory, 1988. In one such technique, an immunogen comprising theantigenic polypeptide is initially injected into any of a wide varietyof mammals (e.g., mice, rats, rabbits, sheep and goats). The immunogenis injected into the animal host, preferably according to apredetermined schedule incorporating one or more booster immunizations,and the animals are bled periodically. Polyclonal antibodies specificfor the polypeptide may then be purified from such antisera by, forexample, affinity chromatography using the polypeptide coupled to asuitable solid support.

Monoclonal antibodies specific for the antigenic polypeptide of interestmay be prepared, for example, using the technique of Kohler andMilstein, Eur. J. Immunol. 6:511-519, 1976, and improvements thereto.Briefly, these methods involve the preparation of immortal cell linescapable of producing antibodies having the desired specificity (i.e.,reactivity with the polypeptide of interest). Such cell lines may beproduced, for example, from spleen cells obtained from an animalimmunized as described above. The spleen cells may then be immortalizedby fusion with a myeloma cell fusion partner, preferably one that issyngeneic with the immunized animal, using one of a variety oftechniques well known in the art.

Monoclonal antibodies may be isolated from the supernatants of theresulting hybridoma colonies. In addition, various techniques may beemployed to enhance the yield, such as injection of the hybridoma cellline into the peritoneal cavity of a suitable vertebrate host, such as amouse. Monoclonal antibodies may then be harvested from the ascitesfluid or the blood.

Antibodies may be used in diagnostic tests to detect the presence ofmycobacterial antigens using assays similar to those detailed above andother techniques well known to those of skill in the art, therebyproviding a method for detecting mycobacterial infection, such as M.tuberculosis infection, in a patient.

Diagnostic reagents of the present invention may also comprise DNAsequences encoding one or more of the above polypeptides, or one or moreportions thereof For example, primers comprising at least 10 contiguousoligonucleotides of the subject DNA sequences may be used in polymerasechain reaction (PCR) based tests. Similarly, probes comprising at least18 contiguous oligonucleotides of the subject DNA sequences may be usedfor hybridizing to specific sequences. Techniques for both PCR basedtests and hybridization tests are well known in the art. Primers orprobes may thus be used to detect M. tuberculosis and othermycobacterial infections in biological samples, preferably sputum,blood, serum, saliva, cerebrospinal fluid or urine. DNA probes orprimers comprising oligonucleotide sequences described above may be usedalone, in combination with each other, or with previously identifiedsequences, such as the 38 kDa antigen discussed above.

As discussed above, effective vaccines contain at least two differentcomponents. The first is a polypeptide comprising an antigen, which isprocessed by macrophages and other antigen-presenting cells anddisplayed for CD4⁺ T cells or for CD8⁺ T cells. This antigen forms the"specific" target of an immune response. The second component of avaccine is a non-specific immune response amplifier, such as an adjuvantor a liposome, into which the antigen is incorporated. An adjuvantamplifies immune responses to a structurally unrelated compound orpolypeptide. Several adjuvants are prepared from microbes such asBordetella pertussis, M. tuberculosis and M. bovis BCG. Adjuvants mayalso contain components designed to protect polypeptide antigens fromdegradation, such as aluminum hydroxide or mineral oil.

While the antigenic component of a vaccine contains polypeptides thatdirect the immune attack against a specific pathogen, such as M.tuberculosis, the adjuvant is often capable of broad use in manydifferent vaccine formulations. Certain pathogens, such as M.tuberculosis, as well as certain cancers, are effectively contained byan immune attack directed by T cells, known as cell-mediated immunity.Other pathogens, such as poliovirus, also require antibodies produced byB cells for containment. These different classes of immune attack (Tcell or B cell) are controlled by different subpopulations of CD4⁺ Tcells, commonly referred to as Th1 and Th2 cells. A desirable propertyof an adjuvant is the ability to selectively amplify the function ofeither Th1 or Th2 populations of CD4⁺ T cells. As shown below in Example6, M. vaccae and a modified form of autoclaved M. vaccae have been foundto have adjuvant properties. As used herein, the term "modified M.vaccae" includes delipidated M. vaccae cells, deglycolipidated M. vaccaecells and M. vaccae cells that have been both delipidated anddeglycolipidated (hereinafter referred to as DD-M. vaccae). Furthermore,it has been found that M. vaccae produces compounds which amplify theimmune response to M. vaccae antigens, as well as to antigens from othersources. The present invention thus provides methods for enhancingimmune responses to an antigen comprising administering killed M. vaccaecells, M. vaccae culture filtrate or modified M. vaccae cells. Asdetailed below, further studies have demonstrated that this non-specificimmune amplifying effect is due, at least in part, to an M. vaccaepolypeptide having homology to heat shock protein 65 (GroEL), previouslyidentified in M. tuberculosis.

As described below in Example 10, it has also been found thatheat-killed M. vaccae and M. vaccae constituents have cytokinestimulation properties. In particular, it has been found thatheat-killed M. vaccae, lyophilised M. vaccae and DD-M. vaccae stimulatethe production of interleukin 12 (IL-12) from macrophages. Production ofIL-12 from macrophages is known to enhance stimulation of a Th1 immuneresponse.

The following examples are offered by way of illustration and not by wayof limitation.

EXAMPLE 1 Effect of Immunization of Mice with M. vaccae on Tuberculosis

This example illustrates the effect of immunization with M. vaccae or M.vaccae culture filtrate in mice prior to challenge with live M.tuberculosis.

M. vaccae (ATCC Number 15483) was cultured in sterile Medium 90 (yeastextract, 2.5 g/l; tryptone, 5 g/l; glucose, 1 g/l) at 37° C. The cellswere harvested by centrifugation, and transferred into sterileMiddlebrook 7H9 medium (Difco Laboratories, Detroit, Mich., USA) withglucose at 37° C. for one day. The medium was then centrifuged to pelletthe bacteria, and the culture filtrate removed. The bacterial pellet wasresuspended in phosphate buffered saline at a concentration of 10 mg/ml,equivalent to 10¹⁰ M. vaccae organisms per ml. The cell suspension wasthen autoclaved for 15 min at 120° C. The culture filtrate was passagedthrough a 0.45 μm filter into sterile bottles.

As shown in FIG. 1A, when mice were immunized with 1 mg, 100 μg or 10 μgof M. vaccae and infected three weeks later with 5×10⁵ colony formingunits (CFU) of live M. tuberculosis H37Rv, significant protection frominfection was seen. In this example, spleen, liver and lung tissue washarvested from mice three weeks after infection, and live bacillidetermined (expressed as CFU). The reduction in bacilli numbers, whencompared to tissue from non-immunized control mice, exceeded 2 logs inliver and lung tissue, and 1 log in spleen tissue. Immunization of micewith heat-killed M. tuberculosis H37Rv had no significant protectiveeffects on mice subsequently infected with live M tuberculosis H37Rv.

FIG. 1B shows that when mice were immunized with 100 μg of M. vaccaeculture filtrate, and infected three weeks later with 5×10⁵ CFU of M.tuberculosis H37Rv, significant protection was also seen. When spleen,liver and lung tissue was harvested from mice three weeks afterinfection, and live bacilli numbers (CFU) determined, a 1-2 logreduction in numbers, as compared to non-immunized control mice, wasobserved.

EXAMPLE 2 Purification and Characterization of Polypeptides from M.vaccae Culture Filtrate

This example illustrates the preparation of M. vaccae soluble proteinsfrom culture filtrate. Unless otherwise noted, all percentages in thefollowing example are weight per volume.

M. vaccae (ATCC Number 15483) was cultured in sterile Medium 90 at 37°C. The cells were harvested by centrifugation, and transferred intosterile Middlebrook 7H9 medium with glucose at 37° C. for one day. Themedium was then centrifuged (leaving the bulk of the cells) and filteredthrough a 0.45 μm filter into sterile bottles.

The culture filtrate was concentrated by lyophilization, and redissolvedin MilliQ water. A small amount of insoluble material was removed byfiltration through a 0.45 μm membrane. The culture filtrate was desaltedby membrane filtration in a 400 ml Amicon stirred cell which contained a3 kDa molecular weight cut-off (MWCO) membrane. The pressure wasmaintained at 50 psi using nitrogen gas. The culture filtrate wasrepeatedly concentrated by membrane filtration and diluted with wateruntil the conductivity of the sample was less than 1.0 mS. Thisprocedure reduced the 20 1 volume to approximately 50 ml. Proteinconcentrations were determined by the Bradford protein assay (Bio-Rad,Hercules, Calif., USA).

The desalted culture filtrate was fractionated by ion exchangechromatography on a column of Q-Sepharose (Pharmacia Biotech, Uppsala,Sweden) (16×100 mm) equilibrated with 10 mM Tris HCl buffer pH 8.0.Polypeptides were eluted with a linear gradient of NaCl from 0 to 1.0 Min the above buffer system. The column eluent was monitored at awavelength of 280 nm.

The pool of polypeptides eluting from the ion exchange column wasconcentrated in a 400 ml Amicon stirred cell which contained a 3 kDaMWCO membrane. The pressure was maintained at 50 psi using nitrogen gas.The polypeptides were repeatedly concentrated by membrane filtration anddiluted with 1% glycine until the conductivity of the sample was lessthan 0.1 mS.

The purified polypeptides were then fractionated by preparativeisoelectric focusing in a Rotofor device (Bio-Rad, Hercules, Calif.,USA). The pH gradient was established with a mixture of Ampholytes(Pharmacia Biotech) comprising 1.6% pH 3.5-5.0 Ampholytes and 0.4% pH5.0-7.0 Ampholytes. Acetic acid (0.5 M) was used as the anolyte, and 0.5M ethanolamine as the catholyte. Isoelectric focusing was carried out at12W constant power for 6 hours, following the manufacturer'sinstructions. Twenty fractions were obtained.

Fractions from isoelectric focusing were combined, and the polypeptideswere purified on a Vydac C4 column (Separations Group, Hesperia, Calif.,USA) 300 Angstrom pore size, 5 micron particle size (10×250 mm). Thepolypeptides were eluted from the column with a linear gradient ofacetonitrile (0-80% v/v) in 0.05% (v/v) trifluoroacetic acid (TFA). Theflow-rate was 2.0 ml/min and the HPLC eluent was monitored at 220 nm.Fractions containing polypeptides were collected to maximize the purityof the individual samples.

Relatively abundant polypeptide fractions were rechromatographed on aVydac C4 column (Separations Group) 300 Angstrom pore size, 5 micronparticle size (4.6×250 mm). The polypeptides were eluted from the columnwith a linear gradient from 20-60% (v/v) of acetonitrile in 0.05% (v/v)TFA at a flow-rate of 1.0 ml/min. The column eluent was monitored at 220nm. Fractions containing the eluted polypeptides were collected tomaximise the purity of the individual samples. Approximately 20polypeptide samples were obtained and they were analysed for purity on apolyacrylamide gel according to the procedure of Laemmli (Laemmli, U.K., Nature 277:680-685, 1970).

The polypeptide fractions which were shown to contain significantcontamination were further purified using a Mono Q column (PharmaciaBiotech) 10 micron particle size (5×50 mm) or a Vydac Diphenyl column(Separations Group) 300 Angstrom pore size, 5 micron particle size(4.6×250 mm). From a Mono Q column, polypeptides were eluted with alinear gradient from 0-0.5 M NaCl in 10 mM Tris HCl pH 8.0. From a VydacDiphenyl column, polypeptides were eluted with a linear gradient ofacetonitrile (20-60% v/v) in 0.1% TFA. The flow-rate was 1.0 ml/min andthe column eluent was monitored at 220 nm for both columns. Thepolypeptide peak fractions were collected and analysed for purity on a15% polyacrylamide gel as described above.

For sequencing, the polypeptides were individually dried onto Biobrene™(Perlin Elmer/Applied BioSystems Division, Foster City, Calif.)--treatedglass fiber filters. The filters with polypeptide were loaded onto aPerkin Elmer/Applied BioSystems Procise 492 protein sequencer and thepolypeptides were sequenced from the amino terminal end usingtraditional Edman chemistry. The amino acid sequence was determined foreach polypeptide by comparing the retention time of the PTH amino acidderivative to the appropriate PTH derivative standards.

Internal sequences were also determined on some antigens by digestingthe antigen with the endoprotease Lys-C, or by chemically cleaving theantigen with cyanogen bromide. Peptides resulting from either of theseprocedures were separated by reversed-phase HPLC on a Vydac C 18 columnusing a mobile phase of 0.05% (v/v) trifluoroacetic acid with a gradientof acetonitrile containing 0.05% (v/v) TFA (1%/min). The eluent wasmonitored at 214 nm. Major internal peptides were identified by their UVabsorbance, and their N-terminal sequences were determined as describedabove.

Using the procedures described above, six soluble M. vaccae antigens,designated GVc-1, GVc-2, GVc-7, GVc-13, GVc-20 and GVc-22, wereisolated. Determined N-terminal and internal sequences for GVc-1 areshown in SEQ ID NOS: 1, 2 and 3, respectively; the N-terminal sequencefor GVc-2 is shown in SEQ ID NO: 4; internal sequences for GVc-7 areshown in SEQ ID NOS: 5-8; internal sequences for GVc-13 are shown in SEQID NOS: 9-11; internal sequence for GVc-20 is shown in SEQ ID NO: 12;and N-terminal and internal sequences for GVc-22 are shown in SEQ ID NO:56-59, respectively. Each of the internal peptide sequences providedherein begins with an amino acid residue which is assumed to exist inthis position in the polypeptide, based on the known cleavagespecificity of cyanogen bromide (Met) or Lys-C (Lys).

Three additional polypeptides, designated GVc-16, GVc-18 and GVc-21,were isolated employing a preparative sodium dodecylsulfate-polyacrylamide gel electrophoresis (SDS-PAGE) purification stepin addition to the preparative isoelectric focusing procedure describedabove. Specifically, fractions comprising mixtures of polypeptides fromthe preparative isoelectric focusing purification step previouslydescribed were purified by preparative SDS-PAGE on a 15% polyacrylamidegel. The samples were dissolved in reducing sample buffer and applied tothe gel. The separated proteins were transferred to a polyvinylidenedifluoride (PVDF) membrane by electroblotting in 10 mM3-(cyclohexylamino)-1-propanesulfonic acid (CAPS) buffer pH 11containing 10% (v/v) methanol. The transferred protein bands wereidentified by staining the PVDF membrane with Coomassie blue. Regions ofthe PVDF membrane containing the most abundant polypeptide species werecut out and directly introduced into the sample cartridge of the PerkinElmer/Applied BioSystems Procise 492 protein sequencer. Proteinsequences were determined as described above. The N-terminal sequencesfor GVc-16, GVc-18 and GVc-21 are provided in SEQ ID NOS: 13, 14 and 15,respectively.

Additional antigens, designated GVc-12, GVc-14, GVc-15, GVc-17 andGVc-19, were isolated employing a preparative SDS-PAGE purification stepin addition to the chromatographic procedures described above.Specifically, fractions comprising a mixture of antigens from the VydacC4 HPLC purification step previously described were fractionated bypreparative SDS-PAGE on a polyacrylamide gel. The samples were dissolvedin non-reducing sample buffer and applied to the gel. The separatedproteins were transferred to a PVDF membrane by electroblotting in 10 mMCAPS buffer, pH 11 containing 10% (v/v) methanol. The transferredprotein bands were identified by staining the PVDF membrane withCoomassie blue. Regions of the PVDF membrane containing the mostabundant polypeptide species were cut out and directly introduced intothe sample cartridge of the Perkin Elmer/Applied BioSystems Procise 492protein sequencer. Protein sequences were determined as described above.The determined N-terminal sequences for GVc-12, GVc-14, GVc-15, GVc-17and GVc-19 are provided in SEQ ID NOS: 16-20, respectively.

All of the above amino acid sequences were compared to known amino acidsequences in the SwissProt data base (version R32) using the GeneAssistsystem. No significant homologies to the amino acid sequences GVc-2 toGVc-22 were obtained. The amino acid sequence for GVc-1 was found tobear some similarity to sequences previously identified from M. bovisand M. tuberculosis. In particular, GVc-1 was found to have somehomology with M. tuberculosis MPT83, a cell surface protein, as well asMPT70. These proteins form part of a protein family (Harboe et al.,Scand. J. Immunol. 42:46-51, 1995).

Subsequent studies led to the isolation of DNA sequences for GV-13c,GVc-14 and GVc-22 (SEQ ID NO: 142, 107 and 108, respectively). Thecorresponding predicted amino acid sequences for GV-13c, GVc-14 andGVc-22 are provided in SEQ ID NO: 143, 109 and 110, respectively.Further studies with GVc-22 suggested that only a part of the geneencoding GVc-22 was cloned. When sub-cloned into the expression vectorpET16, no protein expression was obtained. Subsequent screening of theM. vaccae BamHI genomic DNA library with the incomplete gene fragmentled to the isolation of the complete gene encoding GVc-22. Todistinguish between the full-length clone and the partial GVc-22, theantigen expressed by the full-length gene was called GV-22B. Thedetermined nucleotide sequence of the gene encoding GV-22B and thepredicted amino acid sequence are provided in SEQ ID NOS: 144 and 145respectively.

Amplifications primers AD86 and AD112 (SEQ ID NO: 60 and 61,respectively) were designed from the amino acid sequence of GVc-1 (SEQID NO: 1) and the M. tuberculosis MPT70 gene sequence. Using theseprimers, a 310 bp fragment was amplified from M. vaccae genomic DNA andcloned into EcoRV-digested vector pBluescript II SK⁺ (Stratagene). Thesequence of the cloned insert is provided in SEQ ID NO: 62. The insertof this clone was used to screen a M. vaccae genomic DNA libraryconstructed in lambda ZAP-Express (Stratagene, La Jolla, Calif.). Theclone isolated contained an open reading frame with homology to the M.tuberculosis antigen MPT83 and was re-named GV-1/83. This gene also hadhomology to the M. bovis antigen MPB83. The determined nucleotidesequence and predicted amino acid sequences are provided in SEQ ID NOS:146 and 147 respectively.

From the amino acid sequences provided in SEQ ID NOS: 1 and 2,degenerate oligonucleotides EV59 and EV61 (SEQ ID NOS: 148 and 149respectively) were designed. Using PCR, a 100 bp fragment was amplified,cloned into plasmid pBluescript II SK⁺ and sequenced (SEQ ID NO: 150)following standard procedures (Maniatis) The cloned insert was used toscreen a M. vaccae genomic DNA library constructed in lambdaZAP-Express. The clone isolated had homology to M. tuberculosis antigenMPT70 and M. bovis antigen MPB70, and was named GV-1/70. The determinednucleotide sequence and predicted amino acid sequence for GV-1/70 areprovided in SEQ ID NOS: 151 and 152 respectively.

For expression and purification, the genes encoding GV1/83, GV1/70,GVc-13, GVc-14 and GV-22B were sub-cloned into the expression vectorpET16 (Novagen, Madison, Wis.). Expression and purification were doneaccording to the manufacturer's protocol.

The purified polypeptides were screened for the ability to induce T-cellproliferation and IFN-γ in peripheral blood cells from immune humandonors. These donors were known to be PPD (purified protein derivativefrom M. tuberculosis) skin test positive and their T cells were shown toproliferate in response to PPD. Donor PBMCs and crude soluble proteinsfrom M. vaccae culture filtrate were cultured in medium comprising RPMI1640 supplemented with 10% (v/v) autologous serum, penicillin (60μg/ml), streptomycin (100 μg/ml), and glutamine (2 mM).

After 3 days, 50 μl of medium was removed from each well for thedetermination of IFN-γ levels, as described below. The plates werecultured for a further 4 days and then pulsed with 1 μCi/well oftritiated thymidine for a further 18 hours, harvested and tritium uptakedetermined using a scintillation counter. Fractions that stimulatedproliferation in both replicates two-fold greater than the proliferationobserved in cells cultured in medium alone were considered positive.

IFN-γ was measured using an enzyme-linked immunosorbent assay (ELISA).ELISA plates were coated with a mouse monoclonal antibody directed tohuman IFN-γ (Endogen, Wobural, Mass. 1 μg/ml phosphate-buffered saline(PBS) for 4 hours at 4° C. Wells were blocked with PBS containing 0.2%Tween 20 for 1 hour at room temperature. The plates were then washedfour times in PBS/0.2% Tween 20, and samples diluted 1:2 in culturemedium in the ELISA plates were incubated overnight at room temperature.The plates were again washed, and a biotinylated polyclonal rabbitanti-human IFN-γ serum (Endogen), diluted to 1 μg/ml in PBS, was addedto each well. The plates were then incubated for 1 hour at roomtemperature, washed, and horseradish peroxidase-coupled avidin A (VectorLaboratories, Burlingame, Calif.) was added at a 1:4,000 dilution inPBS. After a further 1 hour incubation at room temperature, the plateswere washed and orthophenylenediamine (OPD) substrate added. Thereaction was stopped after 10 min with 10% (v/v) HCl. The opticaldensity (OD) was determined at 490 nm. Fractions that resulted in bothreplicates giving an OD two-fold greater than the mean OD from cellscultured in medium alone were considered positive.

Examples of polypeptides containing sequences that stimulate peripheralblood mononuclear cells (PBMC) T cells to proliferate and produce IFN-γare shown in Table 1, wherein (-) indicates a lack of activity, (+/-)indicates polypeptides having a result less than twice higher thanbackground activity of control media, (+) indicates polypeptides havingactivity two to four times above background, and (++) indicatespolypeptides having activity greater than four times above background.

                  TABLE 1                                                         ______________________________________                                        Antigen        Proliferation                                                                           IFN-γ                                          ______________________________________                                        GVc-1          ++        +/-                                                  GVc-2          +         ++                                                   GVc-7          +/-       -                                                    GVc-13         +         ++                                                   GVc-14         ++        +                                                    GVc-15         +         +                                                    GVc-20         +         +                                                    ______________________________________                                    

EXAMPLE 3 Purification and Characterisation of Polypeptides from M.vaccae Culture Filtrate by 2-Dimensional Polyacrylamide GelElectrophoresis

M. vaccae soluble proteins were isolated from culture filtrate using2-dimensional polyacrylamide gel electrophoresis as described below.Unless otherwise noted, all percentages in the following example areweight per volume.

M. vaccae (ATCC Number 15483) was cultured in sterile Medium 90 at 37°C. M. tuberculosis strain H37Rv (ATCC number 27294) was cultured insterile Middlebrook 7H9 medium with Tween 80 and oleicacid/albumin/dextrose/catalase additive (Difco Laboratories, Detroit,Mich.). The cells were harvested by centrifugation, and transferred intosterile Middlebrook 7H9 medium with glucose at 37° C. for one day. Themedium was then centrifuged (leaving the bulk of the cells) and filteredthrough a 0.45 μm filter into sterile bottles. The culture filtrate wasconcentrated by lyophilisation, and redissolved in MilliQ water. A smallamount of insoluble material was removed by filtration through a 0.45 μmmembrane filter.

The culture filtrate was desalted by membrane filtration in a 400 mlAmicon stirred cell which contained a 3 kDa MWCO membrane. The pressurewas maintained at 60 psi using nitrogen gas. The culture filtrate wasrepeatedly concentrated by membrane filtration and diluted with wateruntil the conductivity of the sample was less than 1.0 mS. Thisprocedure reduced the 20 1 volume to approximately 50 ml. Proteinconcentrations were determined by the Bradford protein assay (Bio-Rad,Hercules, Calif., USA).

The desalted culture filtrate was fractionated by ion exchangechromatography on a column of Q-Sepharose (Pharmacia Biotech) (16×100mm) equilibrated with 10 mM TrisHCl buffer pH 8.0. Polypeptides wereeluted with a linear gradient of NaCl from 0 to 1.0 M in the abovebuffer system. The column eluent was monitored at a wavelength of 280nm.

The pool of polypeptides eluting from the ion exchange column werefractionated by preparative 2D gel electrophoresis. Samples containing200-500 μg of polypeptide were made 8 M in urea and applied topolyacrylamide isoelectric focusing rod gels (diameter 2 mm, length 150mm, pH 5-7). After the isoelectric focusing step, the first dimensiongels were equilibrated with reducing buffer and applied to seconddimension gels (16% polyacrylamide). FIGS. 2A and 2B are the 2-D gelpatterns observed with M. vaccae culture filtrate and M. tuberculosisH37Rv culture filtrate, respectively. Polypeptides from the seconddimension separation were transferred to PVDF membranes byelectroblotting in 10 mM CAPS buffer pH 11 containing 10% (v/v)methanol. The PVDF membranes were stained for protein with Coomassieblue. Regions of PVDF containing polypeptides of interest were cut outand directly introduced into the sample cartridge of the PerkinElmer/Applied BioSystems Procise 492 protein sequencer. The polypeptideswere sequenced from the amino terminal end using traditional Edmanchemistry. The amino acid sequence was determined for each polypeptideby comparing the retention time of the PTH amino acid derivative to theappropriate PTH derivative standards. Using these procedures, elevenpolypeptides, designated GVs-1, GVs-3, GVs-4, GVs-5, GVs-6, GVs-8,GVs-9, GVs-10, GVs-11, GV-34 and GV-35 were isolated. The determinedN-terminal sequences for these polypeptides are shown in SEQ ID NOS:21-29, 63 and 64, respectively. Using the purification proceduredescribed above, more protein was purified to extend the amino acidsequence previously obtained for GVs-9. The extended amino acid sequencefor GVs-9 is provided in SEQ ID NO: 65. Further studies resulted in theisolation of DNA sequences for GVs-9 (SEQ ID NO: 111) and GV-35 (SEQ IDNO: 155. The corresponding predicted amino acid sequences are providedin SEQ ID NO: 112 and 156, respectively. An extended DNA sequence forGVs-9 is provided in SEQ ID NO: 153, with the corresponding predictedamino acid sequence being provided in SEQ ID NO: 154.

All of these amino acid sequences were compared to known amino acidsequences in the SwissProt data base (version R32) using the GeneAssistsystem. No significant homologies were obtained, with the exceptions ofGVs-3, GVs-4, GVs-5 and GVs-9. GVs-9 was found to bear some homology totwo previously identified M. tuberculosis proteins, namely M.tuberculosis cutinase precursor and an M. tuberculosis hypothetical 22.6kDa protein. GVs-3, GVs-4 and GVs-5 were found to bear some similarityto the antigen 85A and 85B proteins from M. leprae (SEQ ID NOS: 30 and31, respectively), M. tuberculosis (SEQ ID NOS: 32 and 33, respectively)and M. bovis (SEQ ID NOS: 34 and 35, respectively), and the antigen 85Cproteins from M. leprae (SEQ ID NO: 36) and M. tuberculosis (SEQ ID NO:37). A comparison of the inventive antigen 85A protein from M. vaccaewith those from M. tuberculosis, M. bovis and M. leprae, is presented inFIG. 3.

EXAMPLE 4 DNA Cloning Strategy for the M. vaccae Antigen 85 Series

Probes for antigens 85A, 85B, and 85C were prepared by the polymerasechain reaction (PCR) using degenerate oligonucleotides (SEQ ID NOS: 38and 39) designed to regions of antigen 85 genomic sequence that areconserved between family members in a given mycobacterial species, andbetween mycobacterial species. These oligonucleotides were used underreduced stringency conditions to amplify target sequences from M. vaccaegenomic DNA. An appropriately-sized 485 bp band was identified,purified, and cloned into T-tailed p Bluescript II SK (Stratagene, LaJolla, Calif.). Twenty-four individual colonies were screened at randomfor the presence of the antigen 85 PCR product, then sequenced using thePerkin Elmer/Applied Biosystems Model 377 automated sequencer and theM13-based primers, T3 and T7. Homology searches of the GenBank databasesshowed that twenty-three clones contained insert with significanthomology to published antigen 85 genes from M. tuberculosis and M.bovis. Approximately half were most homologous to antigen 85C genesequences, with the remainder being more similar to antigen 85Bsequences. In addition, these two putative M. vaccae antigen 85 genomicsequences were 80% homologous to one another. Because of this highsimilarity, the antigen 85C PCR fragment was chosen to screen M. vaccaegenomic libraries at low stringency for all three antigen 85 genes.

An M. vaccae genomic library was created in lambda Zap-Express(Stratagene, La Jolla, Calif.) by cloning BamHI partially-digested M.vaccae genomic DNA into similarly-digested X vector, with 3.4×10⁵independent plaque-forming units resulting. For screening purposes,twenty-seven thousand plaques from this non-amplified library wereplated at low density onto eight 100 cm² plates. For each plate,duplicate plaque lifts were taken onto Hybond-N⁺ nylon membrane(Amersham International, United Kingdom), and hybridised underreduced-stringency conditions (55° C.) to the radiolabelled antigen 85CPCR product. Autoradiography demonstrated that seventy-nine plaquesconsistently hybridised to the antigen 85C probe under these conditions.Thirteen positively-hybridising plaques were selected at random forfurther analysis and removed from the library plates, with each positiveclone being used to generate secondary screening plates containing abouttwo hundred plaques. Duplicate lifts of each plate were taken usingHybond-N⁺ nylon membrane, and hybridised under the conditions used inprimary screening. Multiple positively-hybridising plaques wereidentified on each of the thirteen plates screened. Two well-isolatedpositive phage from each secondary plate were picked for furtheranalysis. Using in vitro excision, twenty-six plaques were convertedinto phagemid, and restriction-mapped. It was possible to group clonesinto four classes on the basis of this mapping. Sequence data from the5' and 3' ends of inserts from several representatives of each group wasobtained using the Perkin Elmer/Applied Biosystems Model 377 automatedsequencer and the T3 and T7 primers. Sequence homologies were determinedusing FASTA analysis of the GenBank databases with the GeneAssistsoftware package. Two of these sets of clones were found to behomologous to M. bovis and M. tuberculosis antigen 85A genes, eachcontaining either the 5' or 3' ends of the M. vaccae gene (this gene wascleaved during library construction as it contains an internal BamHIsite). The remaining clones were found to contain sequences homologousto antigens 85B and 85C from a number of mycobacterial species. Todetermine the remaining nucleotide sequence for each gene, appropriatesubclones were constructed and sequenced. Overlapping sequences werealigned using the DNA Strider software. The determined DNA sequences forM. vaccae antigens 85A, 85B and 85C are shown in SEQ ID NOS: 40-42,respectively, with the predicted amino acid sequences being shown in SEQID NOS: 43-45, respectively.

The M. vaccae antigens GVs-3 and GVs-5 were expressed and purified asfollows. Amplification primers were designed from the insert sequencesof GVs-3 and GVs-5 (SEQ ID NO: 40 and 42, respectively) using sequencedata downstream from the putative leader sequence and the 3' end of theclone. The sequences of the primers for GVs-3 are provided in SEQ ID NO:66 and 67, and the sequences of the primers for GVs-5 are provided inSEQ ID NO: 68 and 69. A XhoI restriction site was added to the primersfor GVs-3, and EcoRI and BamHI restriction sites were added to theprimers for GVs-5 for cloning convenience. Following amplification fromgenomic M. vaccae DNA, fragments were cloned into the appropriate siteof pProEX HT prokaryotic expression vector (Gibco BRL, LifeTechnologies, Gaithersburg, Md.) and submitted for sequencing to confirmthe correct reading frame and orientation. Expression and purificationof the recombinant protein was performed according to the manufacturer'sprotocol.

Expression of a fragment of the M. vaccae antigen GVs-4 (antigen 85Bhomolog) was performed as follows. The primers AD58 and AD59, describedabove, were used to amplify a 485 bp fragment from M. vaccae genomicDNA. This fragment was gel-purified using standard techniques and clonedinto EcoRV-digested pBluescript containing added dTTP residues. The basesequences of inserts from five clones were determined and found to beidentical to each other. These inserts had highest homology to Ag85Bfrom M. tuberculosis. The insert from one of the clones was subclonedinto the EcoRI/XhoI sites of pProEX HT prokaryotic expression vector(Gibco BRL), expressed and purified according to the manufacturer'sprotocol. This clone was renamed GV-4P because only a part of the genewas expressed. The amino acid and DNA sequences for the partial cloneGV-4P are provided in SEQ ID NO: 70 and 106, respectively.

Similar to the cloning of GV-4P, the amplification primers AD58 and AD59were used to amplify a 485 bp fragment from a clone containing GVs-5(SEQ ID NO: 42). This fragment was cloned into the expression vectorpET16 and was called GV-5P. The determined nucleotide sequence andpredicted amino acid sequence of GV-5P are provided in SEQ ID NOS: 157and 158, respectively.

In subsequent studies, using procedures similar to those describedabove, GVs-3, GV-4P and GVs-5 were re-cloned into the alternative vectorpET16 (Novagen, Madison, Wis.).

The ability of purified recombinant GVs-3, GV-4P and GVs-5 to stimulateproliferation of T cells and interferon-γ production in human PBL fromPPD-positive, healthy donors, was assayed as described above in Example2. The results of this assay are shown in Table 2, wherein (-) indicatesa lack of activity, (+/-) indicates polypeptides having a result lessthan twice higher than background activity of control media, (+)indicates polypeptides having activity two to four times abovebackground, (++) indicates polypeptides having activity greater thanfour times above background, and ND indicates not determined.

                                      TABLE 2                                     __________________________________________________________________________    Donor     Donor Donor Donor Donor Donor                                       G97005    G97006                                                                              G97007                                                                              G97008                                                                              G97009                                                                              G97010                                      Prolif IFN-γ                                                                      Prolif                                                                           IFN-γ                                                                      Prolif                                                                           IFN-γ                                                                      Prolif                                                                           IFN-γ                                                                      Prolif                                                                           IFN-γ                                                                      Prolif                                                                           IFN-γ                              __________________________________________________________________________    GVs-3                                                                             ++ +  ND ND ++ ++ ++ ++ ++ +/±                                                                           +  ++                                       GV-4P                                                                             +  +/-                                                                              ND ND +  ++ ++ ++ +/-                                                                              +/-                                                                              +/-                                                                              ++                                       GVs-5                                                                             ++ ++ ++ ++ ++ ++ +  ++ ++ +  +  ++                                       __________________________________________________________________________

EXAMPLE 5 DNA Cloning Strategy for M. vaccae Antigens

An 84 bp probe for the M. vaccae antigen GVc-7 was amplified usingdegenerate oligonucleotides designed to the determined amino acidsequence of GVc-7 (SEQ ID NOS: 5-8). This probe was used to screen a M.vaccae genomic DNA library as described in Example 4. The determinednucleotide sequence for GVc-7 is shown in SEQ ID NO: 46 and predictedamino acid sequence in SEQ ID NO: 47. Comparison of these sequences withthose in the databank revealed homology to a hypothetical 15.8 kDamembrane protein of M. tuberculosis.

The sequence of SEQ ID NO: 46 was used to design amplification primers(provided in SEQ ID NO: 71 and 72) for expression cloning of the GVc-7gene using sequence data downstream from the putative leader sequence. AXhoI restriction site was added to the primers for cloning convenience.Following amplification from genomic M. vaccae DNA, fragments werecloned into the XhoI-site of pProEX HT prokaryotic expression vector(Gibco BRL) and submitted for sequencing to confirm the correct readingframe and orientation. Expression and purification of the fusion proteinwas performed according to the manufacturer's protocol. In subsequentstudies, GVc-7 was re-cloned into the vector pET16 (Novagen).

The ability of purified recombinant GVc-7 to stimulate proliferation ofT-cells and stimulation of interferon-γ production in human PBL, fromPPD-positive, healthy donors, was assayed as described previously inExample 2. The results are shown in Table 3, wherein (-) indicates alack of activity, (+/-) indicates polypeptides having a result less thantwice higher than background activity of control media, (+) indicatespolypeptides having activity two to four times above background, and(++) indicates polypeptides having activity greater than four timesabove background.

                  TABLE 3                                                         ______________________________________                                        Donor        Proliferation                                                                           Interferon-γ                                     ______________________________________                                        G97005       ++        +/-                                                    G97008       ++        +                                                      G97009       +         +/-                                                    G97010       +/-       ++                                                     ______________________________________                                    

A redundant oligonucleotide probe (SEQ ID NO 73, referred to as MPG15)was designed to the GVs-8 peptide sequence shown in SEQ ID NO: 26 andused to screen a M. vaccae genomic DNA library using standard protocols.A genomic clone containing genes encoding four different antigens wasisolated. The determined DNA sequences for GVs-8A (re-named GV-30),GVs-8B (re-named GV-3 1), GVs-8C (re-named GV-32) and GVs-8D, re-namedGV-33, are shown in SEQ ID NOS: 48-51, respectively, with thecorresponding amino acid sequences being shown in SEQ ID NOS: 52-55,respectively. GV-30 contains regions showing some similarity to knownprokaryotic valyl-tRNA synthetases; GV-31 shows some similarity to M.smegmatis aspartate semialdehyde dehydrogenase; and GV-32 shows somesimilarity to the H. influenza folylpolyglutamate synthase gene. GV-33contains an open reading frame which shows some similarity to sequencespreviously identified in M. tuberculosis and M. leprae, but whosefunction has not been identified.

The determined partial DNA sequence for GV-33 is provided in SEQ IDNO:74 with the corresponding predicted amino acid sequence beingprovided in SEQ ID NO: 75. Sequence data from the 3' end of the cloneshowed homology to a previously identified 40.6 kDaa outer membraneprotein of M. tuberculosis. Subsequent studies led to the isolation of afull-length DNA sequence for GV-33 (SEQ ID NO: 193). The correspondingpredicted amino acid sequence is provided in SEQ ID NO: 194.

The gene encoding GV-33 was amplified from M. vaccae genomic DNA withprimers based on the determined nucleotide sequence. This DNA fragmentwas cloned into EcoRv-digested pBluescript II SK⁺ (Stratagene), and thentransferred to pET16 expression vector. Recombinant protein was purifiedfollowing the manufacturer's protocol.

The ability of purified recombinant GV-33 to stimulate proliferation ofT-cells and stimulation of interferon-γ production in human PBL wasassayed as described previously in Example 2. The results are shown inTable 4, wherein (-) indicates a lack of activity, (+/-) indicatespolypeptides having a result less than twice higher than backgroundactivity of control media, (+) indicates polypeptides having activitytwo to four times above background, and (++) indicates polypeptideshaving activity greater than four times above background.

                  TABLE 4                                                         ______________________________________                                        Stimulatory Activity of Polypeptides                                          Donor        Proliferation                                                                           Interferon-γ                                     ______________________________________                                        G97005       ++        +                                                      G97006       ++        ++                                                     G97007       -         +/-                                                    G97008       +/-       -                                                      G97009       +/-       -                                                      G97010       +/-       ++                                                     ______________________________________                                    

EXAMPLE 6 Detection of Nonspecific Immune Amplifier from Whole M. vaccaeand the Culture Filtrate of M. vaccae

This example illustrates the preparation of whole M. vaccae and M.vaccae culture filtrate and its non-specific immune amplifying or`adjuvant` property.

M. vaccae bacteria was cultured, pelleted and autoclaved as described inExample 1. Culture filtrates of live M. vaccae refer to the supernatantfrom 24 hour cultures of M. vaccae in 7H9 medium with glucose. Adelipidated form of M. vaccae was prepared by sonicating autoclaved M.vaccae for four bursts of 30 seconds on ice using the Virsonic sonicator(Virtis, Disa, USA). The material was then centrifuged (9000 rpm, 20minutes, JA10 rotor, brake=5). The resulting pellet was suspended in 100ml of chloroform/methanol (2:1), incubated at room temperature for 1hour; re-centrifuged, and the chloroform/methanol extraction repeated.The pellet was obtained by centrifugation, dried in vacuo, weighed andresuspended in PBS at 50 mg (dry weight) per ml as delipidated M.vaccae.

Glycolipids were removed from the delipidated M. vaccae preparation byrefluxing in 50% v/v ethanol for 2 hours. The insoluble material wascollected by centrifugation (10,000 rpm, JA20 rotor, 15 mins, brake=5).The extraction with 50% v/v ethanol under reflux was repeated twicemore. The insoluble material was collected by centrifugation and washedin PBS. Proteins were extracted by resuspending the pellet in 2% SDS inPBS at 56° C. for 2 hours. The insoluble material was collected bycentrifugation and the extraction with 2% SDS/PBS at 56° C. was repeatedtwice more. The pooled SDS extracts were cooled to 4° C., andprecipitated SDS was removed by centrifugation (10,000 rpm, JA20 rotor,15 mins, brake=5). Proteins were precipitated from the supernatant byadding an equal volume of acetone and incubating at -20° C. for 2 hours.The precipitated proteins were collected by centrifugation, washed in50% v/v acetone, dried in vacuo, and redissolved in PBS.

M. vaccae culture supernatant (S/N), killed M. vaccae and delipidated M.vaccae were tested for adjuvant activity in the generation of cytotoxicT cell immune response to ovalbumin, a structurally unrelated protein,in the mouse. This anti-ovalbumin-specific cytotoxic response wasdetected as follows. C57BL/6 mice (2 per group) were immunized by theintraperitoneal injection of 100 μg of ovalbumin with the following testadjuvants: autoclaved M. vaccae; delipidated M vaccae; delipidated M.vaccae with glycolipids also extracted and proteins extracted with SDS;the SDS protein extract treated with Pronase (an enzyme which degradesprotein); whole M. vaccae culture filtrate; and heat-killed M.tuberculosis or heat-killed M. bovis BCG, M. phlei or M. smegmatis or M.vaccae culture filtrate. After 10 days, spleen cells were stimulated invitro for a further 6 days with E.G7 cells which are EL4 cells (aC57BL/6-derived T cell lymphoma) transfected with the ovalbumin gene andthus express ovalbumin. The spleen cells were then assayed for theirability to kill non-specifically EL4 target cells or to killspecifically the E.G7 ovalbumin expressing cells. Killing activity wasdetected by the release of 51 Chromium with which the EL4 and E.G7 cellshave been labelled (100 μCi per 2×10⁶), prior to the killing assay.Killing or cytolytic activity is expressed as % specific lysis using theformula: ##EQU1##

It is generally known that ovalbumin-specific cytotoxic cells aregenerated only in mice immunized with ovalbumin with an adjuvant but notin mice immunized with ovalbumin alone.

The diagrams that make up FIG. 4 show the effect of various M. vaccaederived adjuvant preparations on the generation of cytotoxic T cells toovalbumin in C57BL/6 mice. As shown in FIG. 4A, cytotoxic cells weregenerated in mice immunized with (i) 10 μg, (ii) 100 μg or (iii) 1 mg ofautoclaved M. vaccae or (iv) 75 μg of M. vaccae culture filtrate. FIG.4B shows that cytotoxic cells were generated in mice immunized with (i)1 mg whole autoclaved M. vaccae or (ii) 1 mg delipidated anddeglycolipidated (DD-) M. vaccae. As shown in FIG. 4C(i), cytotoxiccells were generated in mice immunized with 1 mg whole autoclaved M.vaccae; FIG. 4C(ii) shows the active material in M. vaccae solubleproteins extracted with SDS from DD-M. vaccae. FIG. 4C(iii) shows thatactive material in the adjuvant preparation of FIG. 4C(ii) was destroyedby treatment with the proteolytic enzyme Pronase. By way of comparison,100 μg of the SDS-extracted proteins had significantly strongerimmune-enhancing ability (FIG. 4C(ii)) than did 1 mg whole autoclaved M.vaccae (FIG. 4C(i)).

Mice immunized with 1 mg heat-killed M. vaccae (FIG. 4D(i)) generatedcytotoxic cells to ovalbumin, but mice immunized separately with 1 mgheat-killed M. tuberculosis (FIG. 4D(ii)), 1 mg M. bovis BCG (FIG.4D(iii)), 1 mg M. phlei (FIG. 4D(iv)), or 1 mg M. smegmatis (FIG. 4D(v))failed to generate cytotoxic cells.

These findings demonstrate that heat-killed M. vaccae and DD-M. vaccaehave adjuvant properties not seen in other mycobacteria. Furthermore,delipidation and deglycolipidation of M. vaccae removes an NKcell-stimulating activity but does not result in a loss of T-cellstimulating activity.

The SDS-extracted proteins derived from delipidated and deglycolipidatedM. vaccae were analysed by polyacrylamide gel electrophoresis. As shownin FIG. 5, three major bands were observed after staining with silver.

In subsequent studies, more of the SDS-extracted proteins describedabove were prepared by preparative SDS-PAGE on a BioRad Prep Cell(Hercules, Calif.). Fractions corresponding to molecular weight rangeswere precipitated by trichloroacetic acid to remove SDS before assayingfor adjuvant activity in the anti-ovalbumin-specific cytotoxic responseassay in C57BL/6 mice as described above. As seen in FIG. 6, theadjuvant activity was highest in the 60-70 kDa a fraction. The mostabundant protein in this size range was purified by SDS-PAGE blotted onto a polyvinylidene difluoride (PVDF) membrane and then sequenced. Thesequence of the first ten amino acid residues is provided in SEQ IDNO:76. Comparison of this sequence with those in the gene bank asdescribed above, revealed homology to the heat shock protein 65 (GroEL)gene from M. tuberculosis, indicating that this protein is an M. vaccaemember of the GroEL family.

An expression library of M. vaccae genomic DNA in BamH1-lambda ZAP-Express (Stratagene) was screened using sera from cynomolgous monkeysimmunised with M. vaccae secreted proteins prepared as described above.Positive plaques were identified using a colorimetric system. Theseplaques were re-screened until plaques were pure following standardprocedures. pBK-CMV phagemid 2-1 containing an insert was excised fromthe lambda ZAP Express (Stratagene) vector in the presence of ExAssisthelper phage following the manufacturer's protocol. The base sequence ofthe 5' end of the insert of this clone, hereinafter referred to asGV-27, was determined using Sanger sequencing with fluorescent primerson Perkin Elmer/Applied Biosystems Dvision automatic sequencer. Thedetermined nucleotide sequence of the partial M. vaccae GroEL-homologueclone GV-27 is provided in SEQ ID NO: 77 and the predicted amino acidsequence in SEQ ID NO: 78. This clone was found to have homology to M.tuberculosis GroEL. A partial sequence of the 65 kDa heat shock proteinof M. vaccae has been published by Kapur et al. (Arch Pathol. Lab. Med.119 :131-138, 1995). The nucleotide sequence of the Kapur et al.fragment is shown in SEQ ID NO: 79 and the predicted amino acid sequencein SEQ ID NO: 80.

In subsequent studies, an extended (full-length except for the predicted51 terminal nucleotides) DNA sequence for GV-27 was obtained (SEQ ID NO:113). The corresponding predicted amino acid sequence is provided in SEQID NO: 114. Further studies led to the isolation of a full-length DNAsequence for GV-27 (SEQ ID NO: 159). The corresponding predicted aminoacid sequence is provided in SEQ ID NO: 160. GV-27 was found to be 93.7%identical to the M. tuberculosis GroEL at the amino acid level.

Two peptide fragments, comprising the N-terminal sequence (hereinafterreferred to as GV-27A) and the carboxy terminal sequence of GV-27(hereinafter referred to as GV-27B) were prepared using techniques wellknown in the art. The nucleotide sequences for GV-27A and GV-27B areprovided in SEQ ID NO: 115 and 116, respectively, with the correspondingamino acid sequences being provided in SEQ ID NO: 117 and 118.Subsequent studies led to the isolation of an extended DNA sequence forGV-27B. This sequence is provided in SEQ ID NO: 161, with thecorresponding amino acid sequence being provided in SEQ ID NO: 162. Thesequence of GV-27A is 95.8% identical to the M. tuberculosis GroELsequence and contains the shorter M. vaccae sequence of Kapur et al.discussed above. The sequence for GV-27B shows about 92.2% identity tothe corresponding region of M tuberculosis HSP65.

Following the same protocol as for the isolation of GV-27, pBK-CMVphagemid 3-1 was isolated. The antigen encoded by this DNA was namedGV-29. The determined nucleotide sequences of the 5' and 3' ends of thegene are provided in SEQ ID NOS: 163 and 164, respectively, with thepredicted corresponding amino acid sequences being provided in SEQ IDNOS: 165 and 166 respectively. GV-29 showed homology to yeast ureaamidolyase. The DNA encoding GV-29 was sub-cloned into the vector pET16(Novagen, Madison, Wis.) for expression and purification according tostandard protocols.

The M. vaccae culture filtrate described above was also fractionated byiso-electric focusing and the fractions assayed for adjuvant activity inthe anti-ovalbumin-specific cytotoxic response assay in C57BL/6 mice asdescribed above. As shown in FIG. 7, peak adjuvant activities weredemonstrated in fractions corresponding to pI of 4.2-4.32 (fraction nos.7-9), 4.49-4.57 (fraction nos. 13-17) and 4.81-5.98 (fraction nos.23-27).

EXAMPLE 7 Autoclaved M. vaccae Generates Cytotoxid CD8 T Cells AgainstM. Tuberculosis Infected Macrophages

This example illustrates the ability of killed M. vaccae to stimulatecytotoxic CD8 T cells which preferentially kill macrophages that havebeen infected with M. tuberculosis.

Mice were immunized by the intraperitoneal injection of 500 μg of killedM. vaccae which was prepared as described in Example 1. Two weeks afterimmunization, the spleen cells of immunized mice were passed through aCD8 T cell enrichment column (R&D Systems, St. Paul, Minn., USA). Thespleen cells recovered from the column have been shown to be enriched upto 90% CD8 T cells. These T cells, as well as CD8 T cells from spleensof non-immunized mice, were tested for their ability to kill uninfectedmacrophages or macrophages which have been infected with M.tuberculosis.

Macrophages were obtained from the peritoneal cavity of mice five daysafter they have been given 1 ml of 3% thioglycolate intraperitoneally.The macrophages were infected overnight with M. tuberculosis at theratio of 2 mycobacteria per macrophage. All macrophage preparations werelabelled with ⁵¹ Chromium at 2 μci per 10⁴ macrophages. The macrophageswere then cultured with CD8 T cells overnight (16 hours) at killer totarget ratios of 30:1. Specific killing was detected by the release of⁵¹ Chromium and expressed as % specific lysis, calculated as in Example5.

The production of IFN-γ and its release into medium after 3 days ofco-culture of CD8 T cells with macrophages was measured using anenzyme-linked immunosorbent assay (ELISA). ELISA plates were coated witha rat monoclonal antibody directed to mouse IFN-γ (Pharmigen, San Diego,Calif., USA) in PBS for 4 hours at 4° C. Wells were blocked with PBScontaining 0.2% Tween 20 for 1 hour at room temperature. The plates werethen washed four times in PBS containing 0.2% Tween 20, and samplesdiluted 1:2 in culture medium in the ELISA plates were incubatedovernight at room temperature. The plates were again washed, and abiotinylated monoclonal rat anti-mouse IFN-γ antibody (Pharmigen),diluted to 1 μg/ml in PBS, was added to each well. The plates were thenincubated for 1 hour at room temperature, washed, and horseradishperoxidase-coupled avidin D (Sigma A-3151) was added at a 1:4,000dilution in PBS. After a further 1 hour incubation at room temperature,the plates were washed and OPD substrate added. The reaction was stoppedafter 10 min with 10% (v/v) HCl. The optical density was determined at490 nm. Fractions that resulted in both replicates giving an OD two-foldgreater than the mean OD from cells cultured in medium alone wereconsidered positive.

As shown in Table 5, CD8 T cells from spleens of mice immunized with M.vaccae were cytotoxic for macrophages infected with M tuberculosis anddid not lyse uninfected macrophages. The CD8 T cells from non-immunizedmice did not lyse macrophages. CD8 T cells from naive or non-immunizedmice do produce IFN-γ when cocultured with infected macrophages. Theamount of IFN-γ produced in coculture was greater with CD8 T cellsderived from M. vaccae immunized mice.

                  TABLE 5                                                         ______________________________________                                        EFFECT WITH M. TUBERCULOSIS INFECTED                                          AND UNINFECTED MACROPHAGES                                                               % Specific Lysis                                                              of Macrophages                                                                            IFN-γ (ng/ml)                                    CD8 T cells  uninfected                                                                             infected uninfected                                                                           infected                                ______________________________________                                        Control      0         0       0.7    24.6                                    M. vaccae Immunized                                                                        0        95       2.2    43.8                                    ______________________________________                                    

EXAMPLE 8 DNA Cloning Strategy for the M. vaccae Antigens GV-23, GV-24,GV-25, GV-26, GV-38A and GV-38B

M. vaccae (ATCC Number 15483) was grown in sterile Medium 90 at 37° C.for 4 days and harvested by centrifugation. Cells were resuspended in 1ml Trizol (Gibco BRL, Life Technologies, Gaithersburg, Md.) and RNAextracted according to the standard manufacturer's protocol. Mtuberculosis strain H37Rv (ATCC Number 27294) was grown in sterileMiddlebrooke 7H9 medium with Tween 80™ and oleicacid/albumin/dextrose/catalase additive (Difco Laboratories, Detroit,Mich.) at 37° C. and harvested under appropriate laboratory safetyconditions. Cells were resuspended in 1 ml Trizol (Gibco BRL) and RNAextracted according to the manufacturer's standard protocol.

Total M. tuberculosis and M. vaccae RNA was depleted of 16S and 23Sribosomal RNA (rRNA) by hybridisation of the total RNA fraction tooligonucleotides AD10 and AD 11 (SEQ ID NO: 81 and 82) complementary toM. tuberculosis rRNA. These oligonucleotides were designed frommycobacterial 16S rRNA sequences published by Bottger (FEMS MicrobiolLett. 65:171-176, 1989) and from sequences deposited in the databanks.Depletion was done by hybridisation of total RNA to oligonucleotidesAD10 and AD11 immobilised on nylon membranes (Hybond N, AmershamInternational, United Kingdom). Hybridisation was repeated until rRNAbands were not visible on ethidium bromide-stained agarose gels. Anoligonucleotide, AD12 (SEQ ID NO: 83), consisting of 20 dATP-residues,was ligated to the 3' ends of the enriched mRNA fraction using RNAligase. First strand cDNA synthesis was performed following standardprotocols, using oligonucleotide AD7 (SEQ ID NO: 84) containing apoly(dT) sequence.

The M. tuberculosis and M. vaccae cDNA was used as template forsingle-sided-specific PCR (3S-PCR). For this protocol, a degenerateoligonucleotide ADI (SEQ ID NO: 85) was designed based on conservedleader sequences and membrane protein sequences. After 30 cycles ofamplification using primer AD1 as 5'-primer and AD7 as 3'-primer,products were separated on a urealpolyacrylamide gel. DNA bands uniqueto M. vaccae were excised and re-amplified using primers AD1 and AD7.After gel purification, bands were cloned into pGEM-T (Promega) and thebase sequence determined.

Searches with the determined nucleotide and predicted amino acidsequences of band 12B21 (SEQ ID NOS: 86 and 87, respectively) showedhomology to the pota gene of E. coli encoding the ATP-binding protein ofthe spermidine/putrescine ABC transporter complex published by Furuchiet al. (Jnl. Biol. Chem. 266: 20928-20933, 1991). Thespermidine/putrescine transporter complex of E. coli consists of fourgenes and is a member of the ABC transporter family. The ABC(ATP-binding Cassette) transporters typically consist of four genes: anATP-binding gene, a periplasmic, or substrate binding, gene and twotransmembrane genes. The transmembrane genes encode proteins eachcharacteristically having six membrane-spanning regions. Homologues (bysimilarity) of this ABC transporter have been identified in the genomesof Haemophilus influenza (Fleischmann et al. Science 269 :496-512, 1995)and Mycoplasma genitalium (Fraser, et al. Science, 270:397-403, 1995).

An M. vaccae genomic DNA library constructed in BamH1-digested lambdaZAP Express (Stratagene) was probed with the radiolabelled 238 bp band12B21 following standard protocols. A plaque was purified to purity byrepetitive screening and a phagemid containing a 4.5 kb insert wasidentified by Southern blotting and hybridisation. The nucleotidesequence of the full-length M. vaccae homologue of pota (ATP-bindingprotein) was identified by subcloning of the 4.5 kb fragment and basesequencing. The gene consisted of 1449 bp including an untranslated 5'region of 320 bp containing putative -10 and -35 promoter elements. Thenucleotide and predicted amino acid sequences of the M. vaccae potahomologue are provided in SEQ ID NOS: 88 and 89, respectively.

The nucleotide sequence of the M. vaccae pota gene was used to designprimers EV24 and EV25 (SEQ ID NO: 90 and 91) for expression cloning. Theamplified DNA fragment was cloned into pProEX HT prokaryotic expressionsystem (Gibco BRL) and expression in an appropriate E. coli host wasinduced by addition of 0.6 mM isopropylthio-β-galactoside (IPTG). Therecombinant protein was named GV-23 and purified from inclusion bodiesaccording to the manufacturer's protocol. In subsequent studies, GV-23(SEQ ID NO: 88) was re-cloned into the alternative vector pET16(Novagen).

A 322 bp Sal1-BamH1 subclone at the 3'-end of the 4.5 kb insertdescribed above showed homology to the potd gene, (periplasmic protein),of the spermidine/putrescine ABC transporter complex of E. coli. Thenucleotide sequence of this subclone is shown in SEQ ID NO: 92. Toidentify the gene, the radiolabelled insert of this subclone was used toprobe a M. vaccae genomic DNA library constructed in the Sal1-site oflambda Zap Express (Stratagene) following standard protocols. A clonewas identified of which 1342 bp showed homology with the potd gene of E.coli. The potd homologue of M. vaccae was identified by subcloning andbase sequencing. The determined nucleotide and predicted amino acidsequences are shown in SEQ ID NO: 93 and 94.

For expression cloning, primers EV-26 and EV-27 (SEQ ID NOS: 95-96) weredesigned from the determined M. vaccae potd homologue. The amplifiedfragment was cloned into pProEX HT Prokaryotic expression system (GibcoBRL). Expression in an appropriate E. coli host was induced by additionof 0.6 mM IPTG and the recombinant protein named GV-24. The recombinantantigen was purified from inclusion bodies according to the protocol ofthe supplier. In subsequent studies, GV-24 (SEQ ID NO: 93) was re-clonedinto the alternative vector pET16 (Novagen).

To improve the solubility of the purified recombinant antigen, the geneencoding GV-24, but excluding the signal peptide, was re-cloned into theexpression vector, employing amplification primers EV101 and EV102 (SEQID NOS: 167 and 168). The construct was designated GV-24B. Thenucleotide sequence of GV-24B is provided in SEQ ID NO: 169 and thepredicted amino acid sequence in SEQ ID NO: 170. This fragment wascloned into pET16 for expression and purification of GV-24B according tothe manufacturer's protocols.

The ability of purified recombinant protein GV-23 and GV-24 to stimulateproliferation of T cells and interferon- production in human PBL wasdetermined as described in Example 2. The results of these assays areprovided in Table 6, wherein (-) indicates a lack of activity, (+/-)indicates polypeptides having a result less than twice higher thanbackground activity of control media, (+) indicates polypeptides havingactivity two to four times above background, (++) indicates polypeptideshaving activity greater than four times above background, and (ND)indicates not determined.

                                      TABLE 6                                     __________________________________________________________________________    Donor     Donor Donor Donor Donor Donor                                       G97005    G97006                                                                              G97007                                                                              G97008                                                                              G97009                                                                              G97010                                      Prolif IFN-γ                                                                      Prolif                                                                           IFN-γ                                                                      Prolif                                                                           IFN-γ                                                                      Prolif                                                                           IFN-γ                                                                      Prolif                                                                           IFN-γ                                                                      Prolif                                                                           IFN-γ                              __________________________________________________________________________    GV-23                                                                             ++ ++ ++ ++ +  +  ++ ++ +  -  +  ++                                       GV-24                                                                             ++ +  ++ +  ND ND +  +/-                                                                              +  +/-                                                                              +/-                                                                              ++                                       __________________________________________________________________________

Base sequence adjacent to the M. vaccae potd gene-homologue was found toshow homology to the potb gene of the spermidine/putrescine ABCtransporter complex of E. coli, which is one of two transmembraneproteins in the ABC transporter complex. The M. vaccae potb homologue(referred to as GV-25) was identified through further subcloning andbase sequencing. The determined nucleotide and predicted amino acidsequences for GV-25 are shown in SEQ ID NOS: 97 and 98, respectively.

Further subcloning and base sequence analysis of the adjacent 509 bpfailed to reveal significant homology to PotC, the second transmembraneprotein of E. coli, and suggests that a second transmembrane protein isabsent in the M. vaccae homologue of the ABC transporter. An openreading frame with homology to M. tuberculosis acetyl-CoA acetyltransferase, however, was identified starting 530 bp downstream of thetransmembrane protein and the translated protein was named GV-26. Thedetermined partial nucleotide sequence and predicted amino acid sequencefor GV-26 are shown in SEQ ID NO:99 and 100.

Using a protocol similar to that described above for the isolation ofGV-23, the 3S-PCR band 12B28 (SEQ ID NO: 119) was used to screen the M.vaccae genomic library constructed in the BamHI-site of lambda ZAPExpress (Stratagene). The clone isolated from the library contained anovel open reading frame and the antigen encoded by this gene was namedGV-38A. The determined nucleotide sequence and predicted amino acidsequence of GV-38A are shown in SEQ ID NO: 120 and 121, respectively.Subsequent studies led to the isolation of an extended DNA sequence forGV-38A, provided in SEQ ID NO: 171. The corresponding amino acidsequence is provided in SEQ ID NO: 172. Comparison of these sequenceswith those in the gene bank, revealed some homology to an unknown M.tuberculosis protein previously identified in cosmid MTCY428.12.(SPTREMBL:P71915).

Upstream of the GV-38A gene, a second novel open reading frame wasidentified and the antigen encoded by this gene was named GV-38B. Thedetermined 5' and 3' nucleotide sequences for GV-38B are provided in SEQID NO: 122 and 123, respectively, with the corresponding predicted aminoacid sequences being provided in SEQ ID NO: 124 and 125, respectively.Further studies led to the isolation of the full-length DNA sequence forGV-38B, provided in SEQ ID NO: 173. The corresponding amino acidsequence is provided in SEQ ID NO: 174. This protein was found to showhomology to an unknown M. tuberculosis protein identified in cosmidMTCY428.11 (SPTREMBL: P71914).

Both the GV-38A and GV-38B antigens were amplified for expressioncloning into pET16 (Novagen). GV-38A was amplified with primers KR11 andKR12 (SEQ ID NO: 126 and 127) and GV-38B with primers KR13 and KR14 (SEQID NO: 128 and 129). Protein expression in the host cells BL21(DE3) wasinduced with 1 mM IPTG, however no protein expression was obtained fromthese constructs. Hydrophobic regions were identified in the N-terminiof antigens GV-38A and GV-38B which may inhibit expression of theseconstructs. The hydrophobic region present in GV-38A was identified as apossible transmembrane motif with six membrane spanning regions. Toexpress the antigens without the hydrophobic regions, primers KR20 forGV-38A, (SEQ ID NO: 130) and KR21 for GV-38B (SEQ ID NO: 131) weredesigned. The truncated GV-38A gene was amplified with primers KR20 andKR12, and the truncated GV-38B gene with KR21 and KR14. The determinednucleotide sequences of truncated GV38A and GV-38B are shown in SEQ IDNO: 132 and 133, respectively, with the corresponding predicted aminoacid sequences being shown in SEQ ID NO: 134 and 135, respectively.Extended DNA sequences for truncated GV-38A and GV-38B are provided inSEQ ID NO: 175 and 176, respectively, with the corresponding amino acidsequences being provided in SEQ ID NO: 177 and 178, respectively.

EXAMPLE 9 Purification and Characterisation of Polypeptides from M.vaccae Culture Filtrate by Preparative Isoelectric Focusing andPreparative Polyacrylamide Gel Electrophoresis

M. vaccae soluble proteins were isolated from culture filtrate usingpreparative isoelectric focusing and preparative polyacrylamide gelelectrophoresis as described below. Unless otherwise noted, allpercentages in the following example are weight per volume.

M. vaccae (ATCC Number 15483) was cultured in 250 1 sterile Medium 90which had been fractionated by ultrafiltration to remove all proteins ofgreater than 10 kDa molecular weight. The medium was centrifuged toremove the bacteria, and sterilised by filtration through a 0.45 μmfilter. The sterile filtrate was concentrated by ultrafiltration over a10 kDa molecular weight cut-off membrane.

Proteins were isolated from the concentrated culture filtrate byprecipitation with 10% trichloroacetic acid. The precipitated proteinswere re-dissolved in 100 mM Tris.HCl pH 8.0. and re-precipitated by theaddition of an equal volume of acetone. The acetone precipitate wasdissolved in water, and proteins were re-precipitated by the addition ofan equal volume of chloroform:methanol 2:1 (v/v). Thechloroform:methanol precipitate was dissolved in water, and the solutionwas freeze-dried.

The freeze-dried protein was dissolved in iso-electric focusing buffer,containing 8 M deionised urea, 2% Triton X-100, 10 mM dithiothreitol and2% ampholytes (pH 2.5-5.0). The sample was fractionated by preparativeiso-electric focusing on a horizontal bed of Ultrodex gel at 8 wattsconstant power for 16 hours. Proteins were eluted from the gel bedfractions with water and concentrated by precipitation with 10%trichloroacetic acid.

Pools of fractions containing proteins of interest were identified byanalytical polyacrylamide gel electrophoresis and fractionated bypreparative polyacrylamide gel electrophoresis. Samples werefractionated on 12.5% SDS-PAGE gels, and electroblotted ontonitrocellulose membranes. Proteins were located on the membranes bystaining with Ponceau Red, destained with water and eluted from themembranes with 40% acetonitrile/0.1 M ammonium bicarbonate pH 8.9 andthen concentrated by lyophilisation.

Eluted proteins were assayed for their ability to induce proliferationand interferon-γ secretion from the peripheral blood lymphocytes ofimmune donors as detailed in Example 2. Proteins inducing a strongresponse in these assays were selected for further study.

Selected proteins were further purified by reversed-phase chromatographyon a Vydac Protein C4 column, using a trifluoroacetic acid-acetonitrilesystem. Purified proteins were prepared for protein sequencedetermination by SDS-polyacrylamide gel electrophoresis, andelectroblotted onto PVDF membranes. Protein sequences were determined asin Example 3. The proteins were named GV-40, GV-41, GV-42, GV-43 andGV-44. The determined N-terminal sequences for these polypeptides areshown in SEQ ID NOS: 101-105, respectively. Subsequent studies led tothe isolation of a 5', middle fragment and 3' DNA sequence for GV-42(SEQ ID NO: 136, 137 and 138, respectively). The corresponding predictedamino acid sequences are provided in SEQ ID NO: 139, 140 and 141,respectively.

Following standard DNA amplification and cloning procedures as describedin Example 5, the genes encoding GV-41 and GV-42 were cloned. Thedetermined nucleotide sequences are provided in SEQ ID NOS: 179 and 180,respectively, and the predicted amino acid sequences in SEQ ID NOS: 181and 182. GV-41 had homology to the ribosome recycling factor of M.tuberculosis and M. leprae, and GV-42 had homogy to a M. aviumfibronectin attachment protein FAP-A. Within the full-length sequence ofGV-42, the amino acid sequence determined for GV-43 (SEQ ID NO:104 ) wasidentified, indicating that the amino acid sequences for GV-42 and GV-43were obtained from the same protein.

Murine polyclonal antisera were prepared against GV-40 and GV-44following standard procedures. These antisera were used to screen a M.vaccae genomic DNA library consisting of randomly sheared DNA fragments.Clones encoding GV-40 and GV-44 were identified and sequenced. Thedetermined nucleotide sequence of the partial gene encoding GV-40 isprovided in SEQ ID NO: 183 and the predicted amino acid sequence in SEQID NO: 184. The determined nucleotide sequence of the gene encodingGV-44 is provided in SEQ ID NO: 185, and the predicted amino acidsequence in SEQ ID NO: 186. Homology of GV-40 to M. leprae Elongationfactor G was found and GV-44 had homology to M. lepraeglyceraldehyde-3-phosphate dehydrogenase.

EXAMPLE 10 Immune Modulating Properties of Delipidated andDeglycolipidated M. vaccae and Recombinant Proteins From M. vaccae

This example illustrates the processing of different constituents of M.vaccae and their immune modulating properties.

Heat-killed M. vaccae and M. vaccae culture filtrate

M. vaccae (ATCC Number 15483) was cultured in sterile Medium 90 (yeastextract, 2.5 g/l; tryptone, 5 g/l; glucose 1 g/l) at 37° C. The cellswere harvested by centrifugation, and transferred into sterileMiddlebrook 7H9 medium (Difco Laboratories, Detroit, Mich., USA) withglucose at 37° C. for one day. The medium was then centrifuged to pelletthe bacteria, and the culture filtrate removed. The bacterial pellet wasresuspended in phosphate buffered saline at a concentration of 10 mg/ml,equivalent to 10¹⁰ M. vaccae organisms per ml. The cell suspension wasthen autoclaved for 15 min at 120° C. The culture filtrate was passagedthrough a 0.45 μm filter into sterile bottles.

Preparation of Delipidated and Deglycolipidated (DD-) M. vaccae andCompositional Analysis

To prepare delipidated M. vaccae, the autoclaved M. vaccae was pelletedby centrifugation, the pellet washed with water and collected again bycentrifugation and then freeze-dried. An aliquot of this freeze-dried M.vaccae was set aside and referred to as lyophilised M. vaccae. When usedin experiments it was resuspended in PBS to the desired concentration.Freeze-dried M. vaccae was treated with chloroform/methanol (2:1) for 60mins at room temperature to extract lipids, and the extraction wasrepeated once. The delipidated residue from chloroform/methanolextraction was further treated with 50% ethanol to remove glycolipids byrefluxing for two hours. The 50% ethanol extraction was repeated twotimes. The pooled 50% ethanol extracts were used as a source of M.vaccae glycolipids (see below). The residue from the 50% ethanolextraction was freeze-dried and weighed. The amount of delipidated anddeglycolipidated M. vaccae prepared was equivalent to 11.1% of thestarting wet weight of M. vaccae used. For bioassay, the delipidated anddeglycolipidated M. vaccae (DD-M. vaccae; referred to as delipidated M.vaccae in FIG. 9), was resuspended in phosphate-buffered saline bysonication, and sterilised by autoclaving.

The compositional analyses of heat-killed M. vaccae and DD-M. vaccae arepresented in Table 7. Major changes are seen in the fatty acidcomposition and amino acid composition of DD-M. vaccae as compared tothe insoluble fraction of heat-killed M. vaccae. The data presented inTable 1 show that the insoluble fraction of heat-killed M. vaccaecontains 10% w/w of lipid, and the total amino acid content is 2750nmoles/mg, or approximately 33% w/w. DD-M. vaccae contains 1.3% w/w oflipid and 4250 nmoles/mg amino acids, which is approximately 51% w/w.

                  TABLE 7                                                         ______________________________________                                        Compositional analyses of heat-killed M. vaccae and DD-M. vaccae              MONOSACCHARIDE COMPOSITION                                                    sugar alditol  M. vaccae                                                                              DD-M. vaccae                                          ______________________________________                                        Inositol       3.2%     1.7%                                                  Ribitol*       1.7%     0.4%                                                  Arabinitol     22.7%    27.0%                                                 Mannitol       8.3%     3.3%                                                  Galactitol     11.5%    12.6%                                                 Glucitol       52.7%    55.2%                                                 ______________________________________                                    

    ______________________________________                                        FATTY ACID COMPOSITION                                                        Fatty acid    M. vaccae                                                                              DD-M. vaccae                                           ______________________________________                                        C14:0         3.9%     10.0%                                                  C16:0         21.1%    7.3%                                                   C16:1         14.0%    3.3%                                                   C18:0         4.0%     1.5%                                                   C18:1*        1.2%     2.7%                                                   C18:1w9       20.6%    3.1%                                                   C18:1w7       12.5%    5.9%                                                   C22:0         12.1%    43.0%                                                  C24:1*        6.5%     22.9%                                                  ______________________________________                                    

The insoluble fraction of heat-killed M. vaccae contains 10% w/w oflipid, and DD-M. vaccae contains 1.3% W/W of lipid.

    ______________________________________                                        AMINO ACID COMPOSITION                                                        Nmoles/mg      M. vaccae                                                                              DD-M. vaccae                                          ______________________________________                                        ASP            231      361                                                   THR            170      266                                                   SER            131      199                                                   GLU            319      505                                                   PRO            216      262                                                   GLY            263      404                                                   ALA            416      621                                                   CYS*            24       26                                                   VAL            172      272                                                   MET*            72       94                                                   ILE            104      171                                                   LEU            209      340                                                   TYR             39       75                                                   PHE             76      132                                                   GlcNH2          5        6                                                    HIS             44       77                                                   LYS            108      167                                                   ARG            147      272                                                   ______________________________________                                    

The total amino acid content of the insoluble fraction of heat-killed M.vaccae is 2750 nmoles/mg, or approximately 33% w/w. The total amino acidcontent of DD-M. vaccae is 4250 nmoles/mg, or approximately 51% w/w.

M. vaccae glycolipids

The pooled 50% ethanol extracts described above were dried by rotaryevaporation, redissolved in water, and freeze-dried. The amount ofglycolipid recovered was 1.2% of the starting wet weight of M. vaccaeused. For bioassay, the glycolipids were dissolved in phosphate-bufferedsaline.

Production of Interleukin-12 from macrophages

Whole heat-killed M. vaccae and DD-M. vaccae were shown to havedifferent cytokine stimulation properties. The stimulation of a Th1immune response is enhanced by the production of interleukin-12 (IL-12)from macrophages. The ability of different M. vaccae preparations tostimulate IL-12 production was demonstrated as follows.

A group of C57BL/6J mice were injected intraperitoneally with DIFCOthioglycolate and after three days, peritoneal macrophages werecollected and placed in cell culture with interferon-gamma for threehours. The culture medium was replaced and various concentrations ofwhole heat-killed (autoclaved) M. vaccae, lyophilized M. vaccae, DD-M.vaccae (referred to as delipidated-deglycolipidated M. vaccae in FIG. 8)and M. vaccae glycolipids were added. After a further three days at 37°C., the culture supernatants were assayed for the presence of IL-12produced by macrophages. As shown in FIG. 8, the M. vaccae preparationsstimulated the production of IL-12 from macrophages.

By contrast, these same M. vaccae preparations were examined for theability to stimulate interferon-gamma production from Natural Killer(NK) cells. Spleen cells were prepared from Severe CombinedImmunodeficient (SCID) mice. These populations contain 75-80% NK cells.The spleen cells were incubated at 37° C. in culture with differentconcentrations of heat-killed M. vaccae, DD-M. vaccae, or M. vaccaeglycolipids. The data shown in FIG. 10 demonstrates that, whileheat-killed M. vaccae and M. vaccae glycolipids stimulate production ofinterferon-gamma, DD-M. vaccae stimulated relatively lessinterferon-gamma. The combined data from FIGS. 8 and 10 indicate that,compared with whole heat-killed M. vaccae, DD-M. vaccae is a betterstimulator of IL-12 than interferon gamma.

FIGS. 9A, B, and C show data from separate experiments in which groupsof C57BL/6 mice (FIG. 9A), BALB/C mice (FIG. 9B) or C3H/HeJ mice (FIG.9C) were given DIFCO thioglycolate intraperitoneally and, after threedays, peritoneal macrophages were collected and placed in culture withinterferon-gamma for three hours. The culture medium was replaced andvarious concentrations of M. vaccae recombinant proteins GVs-3 (GV-3),GV-4P (GV-4P), GVc-7 (GV-7), GV-23, GV-27, heat killed M. vaccae, DD-M.vaccae (referred to as delipidated M. vaccae in FIGS. 9A, B and C), M.vaccae glycolipids or lipopolysaccharide were added. After three days at37° C., the culture supernatants were assayed for the presence of IL-12produced by macrophages. As shown in FIGS. 9A, B and C, the recombinantproteins and M. vaccae preparations stimulated the production of IL-12from macrophages.

EXAMPLE 11 Effect of Intradermal Route of Immunisation with M. vaccae onTuberculosis in Cynomolgous Monkeys

This example illustrates the effect of immunisation with M. vaccae or M.vaccae culture filtrate intradermally in cynomolgous monkeys prior tochallenge with live M. tuberculosis.

M. vaccae (ATCC Number 15483) was cultured in sterile Medium 90 (yeastextract, 2.5 g/l; tryptone, 5 g/l; glucose, 1 g/l) at 37° C. The cellswere harvested by centrifugation, and transferred into sterileMiddlebrook 7H9 medium (Difco Laboratories, Detroit, Mich., USA) withglucose at 37° C. for one day. The medium was then centrifuged to pelletthe bacteria, and the culture filtrate removed. The bacterial pellet wasresuspended in phosphate buffered saline at a concentration of 10mg/ml,equivalent to 10¹⁰ M. vaccae organisms per ml. The cell suspension wasthen autoclaved for 15 min at 120° C. The culture filtrate was passagedthrough a 0.45 μM filter into sterile bottles.

Three groups of cynomolgous monkeys were included in this study, witheach group containing 2 monkeys. One group of monkeys were immunisedwith whole heat-killed M. vaccae; one group were immunised with M.vaccae culture filtrate and a control group received no immunisations.The composition employed for immunisation, amount of immunogen and routeof administration for each group of monkeys are provided in Table 7.

                  TABLE 7                                                         ______________________________________                                        COMPARISON OF INTRADERMAL                                                     ROUTE OF IMMUNISATION                                                                     Identification                                                    Group       Number of Amount of  Route of                                     Number      Monkey    Antigen    Immunisation                                 ______________________________________                                        1           S3101-E   0            --                                         (Controls)  3144-B    0            --                                         2           4080-B    500     μg                                                                              intradermal                                (Immunised  3586-B    500     μg                                                                              intradermal                                with heat-killed                                                              M. vaccae)                                                                    3           3564-B    100     μg                                                                              intradermal                                (Immunised  3815-B    100     μg                                                                              intradermal                                with culture filtrate)                                                        ______________________________________                                    

Prior to immunisation, all monkeys were weighed (Wt kgs), bodytemperature measured (temp), and a blood sample taken for determinationof erythrocyte sedimentation rate (ESR mm/hr) and lymphocyteproliferation (LPA) to an in vitro challenge with purified protein (PPD)prepared from Mycobacterium bovis. At day 33 post-immunisation thesemeasurements were repeated. At day 34, all monkeys received a secondimmunisation using the same amount of M. vaccae. On day 62, body weight,temperature, ESR and LPA to PPD were measured, then all monkeys wereinfected with 103 colony forming units of the Erdman strain of M.tuberculosis. Twenty eight days following infection, body weight,temperature, ESR and LPA to PPD were measured in all monkeys, and thelungs were X-rayed to determine whether infection with live M.tuberculosis had resulted in the onset of pneumonia As shown in Tables8A, B and C, the monkeys in the control group showed radiologic evidenceof pulmonary tuberculosis by 28 days after infection with M.tuberculosis. Clinical disease was not evident 84 days after infectionin monkeys immunised intradermally with two doses of 500 μg of M.vaccae. The onset of clinical disease was delayed in both monkeysimmunised intradermally with 100 μg of M. vaccae culture filtrate.

                  TABLE 8A                                                        ______________________________________                                        CONTROL MONKEYS                                                                                                 LPA  LPA                                                   Wt.          ESR   PPD  PPD                                    ID#   Days     Kgs    Temp. Mm/hr 10 μg                                                                           1 μg                                                                            X-Ray                             ______________________________________                                        S3101E                                                                               0       2.17   37.0  0     0.47 1.1  Negative                                34       1.88   37.3  ND    0.85 1.4  ND                                      62       2.02   36.0  ND    1.3  1.5  ND                                →                                                                            Time of                                                                       Infection                                                                     28       2.09   38.0  2     1.3  3.7  Positive                                56       1.92   37.2  20    5.6  9.1  Positive                                84       1.81   37.5  8     4.7  5.6  Positive                          3144-B                                                                               0       2.05   36.7  0     0.87 1.8  Negative                                34       1.86   37.6  ND    2.2  1.4  ND                                      62       1.87   36.5  ND    1.6  1.6  ND                                →                                                                            Time of                                                                       Infection                                                                     28       2.10   38.0  0     12   8.7  Positive                                56       1.96   37.6  0     29.6 21.1 Positive                                84       1.82   37.3  4     45.3 23.4 Positive                          ______________________________________                                         ND = Not Done                                                            

                  TABLE 8B                                                        ______________________________________                                        MONKEYS IMMUNISED WITH WHOLE HEAT-KILLED M. VACCAE                            (500 μg) INTRADERMALLY                                                                                       LPA  LPA                                                   Wt.          ESR   PPD  PPD                                    ID#   Days     Kgs    Temp. Mm/hr 10 μg                                                                           1 μg                                                                            X-Ray                             ______________________________________                                        4080-B                                                                               0       2.05   37.1  1     1.1  0.77 Negative                                34       1.97   38.0  ND    1.7  1.4  ND                                      62       2.09   36.7  ND    1.5  1.5  ND                                →                                                                            Time of                                                                       Infection                                                                     28       2.15   37.6  0     2.6  2.1  Negative                                56       2.17   37.6  0     8.2  7.6  Negative                                84       2.25   37.3  0     3.8  2.8  Negative                          3586-B                                                                              0        2.29   37.0  0     1.1  1.4  Negative                                34       2.22   38.0  ND    1.9  1.6  ND                                      62       2.39   36.0  ND    1.3  1.6  ND                                →                                                                            Time of                                                                       Infection                                                                     28       2.31   38.2  0     3.2  2.6  Negative                                56       2.32   37.2  0     7.8  4.2  Negative                                84       2.81   37.4  0     3.4  1.8  Negative                          ______________________________________                                         ND = Not Done                                                            

                  TABLE 8C                                                        ______________________________________                                        MONKEYS IMMUNISED WITH CULTURE FILTRATE (100 μg)                           INTRADERMALLY                                                                                                   LPA  LPA                                                   Wt.          ESR   PPD  PPD                                    ID#   Days     Kgs    Temp. Mm/hr 10 μg                                                                           1 μg                                                                            X-Ray                             ______________________________________                                        3564-B                                                                               0       2.40   37.2  0     1.4  1.4  Negative                                34       2.42   38.1  ND    3.3  2.7  ND                                      62       2.31   37.1  ND    3.1  3.4  ND                                →                                                                            Time of                                                                       Infection                                                                     28       2.41   38.6  13    24   13.6 Negative                                56       2.38   38.6  0     12.7 12.0 Negative                                84       2.41   38.6  2     21.1 11.8 Positive                          3815-B                                                                              0        2.31   36.3  0     1.0  1.4  Negative                                34       2.36   38.2  ND    1.9  2.0  ND                                      62       2.36   36.4  ND    3.7  2.8  ND                                →                                                                            Time of                                                                       Infection                                                                     28       2.45   37.8  0     2.1  3.3  Negative                                56       2.28   37.3  4     8.0  5.6  Negative                                84       2.32   37.4  0     1.9  2.2  Positive                          ______________________________________                                         ND = Not Done                                                            

EXAMPLE 12 DNA Cloning Strategy for the DD-M. vaccae Antigen GV-45

Proteins were extracted from DD-M. vaccae (500 mg; prepared as describedin Example 10) by suspension in 10 ml 2% SDS/PBS and heating to 50° C.for 2 h. The insoluble residue was removed by centrifugation, andproteins precipitated from the supernatant by adding an equal volume ofacetone and incubating at -20° C. for 1 hr. The precipitated proteinswere collected by centrifugation, dissolved in reducing sample buffer,and fractionated by preparative SDS-polyacrylamide gel electrophoresis.The separated proteins were electroblotted onto PVDF membrane in 10 mMCAPS/0.0 1% SDS pH 11.0, and N-terminal sequences were determined in agas-phase sequenator.

The amino acid sequence obtained from these experiments was designatedGV-45. The determined N-terminal sequence for GV-45 is provided in SEQID NO: 187.

From the amino acid sequence of GV-45, degenerate oligonucleotides KR32and KR33 (SEQ ID NOS: 188 and 189, respectively) were designed. A 100 bpfragment was amplified, cloned into plasmid pBluescript II SK⁺(Stratagene, La Jolla, Calif.) and sequenced (SEQ ID NO: 190) followingstandard procedures (Maniatis). The cloned insert was used to screen aM. vaccae genomic DNA library constructed in the BamHI-site of lambdaZAP-Express (Stratagene). The isolated clone showed homology to a 35 kDaM. tuberculosis and a 22 kDa M. leprae protein containing bacterialhistone-like motifs at the N-terminus and a unique C-terminus consistingof a five amino acid basic repeat. The determined nucleotide sequencefor GV-45 is provided in SEQ ID NO: 191, with the correspondingpredicted amino acid sequence being provided in SEQ ID NO: 192.

Although the present invention has been described in some detail by wayof illustration and example for purposes of clarity of understanding,changes and modifications can be carried out without departing from thescope of the invention which is intended to be limited only by the scopeof the appended claims.

    __________________________________________________________________________    #             SEQUENCE LISTING                                                - (1) GENERAL INFORMATION:                                                    -    (iii) NUMBER OF SEQUENCES: 194                                           - (2) INFORMATION FOR SEQ ID NO:1:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 25 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1:                                 #Val Gln Gln Val Pro Asply Xaa Ala Ala Tyr                                    #                 15                                                          -  Gly Pro Gly Ser Val Gln Gly Met Ala                                        #             25                                                              - (2) INFORMATION FOR SEQ ID NO:2:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 10 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2:                                 -  Met Xaa Asp Gln Leu Lys Val Asn Asp Asp                                    #                 10                                                          - (2) INFORMATION FOR SEQ ID NO:3:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 11 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3:                                 #Tyret Xaa Pro Val Pro Val Ala Thr Ala Ala                                    #                 10                                                          - (2) INFORMATION FOR SEQ ID NO:4:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 21 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4:                                 #Asp His Val Glu Gln Alaro Pro Pro Tyr Val                                    #                 15                                                          -  Lys Phe Gly Asp Leu                                                                     20                                                               - (2) INFORMATION FOR SEQ ID NO:5:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 29 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5:                                 #Phe Ala Lys Arg Glu Lysla Asp Ala Tyr Ala                                    #                 15                                                          #Phe Glu Threu Ala Pro Gly Val Pro Xaa Val                                    #             25                                                              - (2) INFORMATION FOR SEQ ID NO:6:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 21 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6:                                 #Val Ser Lys Thr Thr Argaa Ala Ile Leu Gln                                    #                 15                                                          -  Gly Gly Gln Ala Ala                                                                     20                                                               - (2) INFORMATION FOR SEQ ID NO:7:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 11 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7:                                 #Arget Pro Ile Leu Gln Val Ser Gln Thr Gly                                    #                 10                                                          - (2) INFORMATION FOR SEQ ID NO:8:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 14 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8:                                 #Val Ser Ser Thrro Ile Xaa Leu Gln Leu Gln                                    #                 10                                                          - (2) INFORMATION FOR SEQ ID NO:9:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 16 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9:                                 #Arg Ile Glu Ala Arg Valln Gly Gly Leu Gly                                    #                 15                                                          - (2) INFORMATION FOR SEQ ID NO:10:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 9 amino                                                           (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:10:                                -  Lys Xaa Gly Leu Ala Asp Leu Ala Pro                                          1               5                                                           - (2) INFORMATION FOR SEQ ID NO:11:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 14 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (ix) FEATURE:                                                                     (A) NAME/KEY: Other                                                           (B) LOCATION: 12...12                                               #Residue can be either Glu or Ile                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:11:                                #Val Xaa Ala Alala Leu Ala Leu Met Ser Ala                                    #                 10                                                          - (2) INFORMATION FOR SEQ ID NO:12:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 11 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:12:                                #Thrys Asn Pro Gln Val Ser Asp Glu Leu Xaa                                    #                 10                                                          - (2) INFORMATION FOR SEQ ID NO:13:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 21 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:13:                                #Asp Pro Ala Ala Val Valla Pro Ala Xaa Gly                                    #                 15                                                          -  Ala Ala Met Ser Thr                                                                     20                                                               - (2) INFORMATION FOR SEQ ID NO:14:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 15 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:14:                                #Gly Glu Leu Val Asnaa Tyr Leu Gly Gln Pro                                    #                 15                                                          - (2) INFORMATION FOR SEQ ID NO:15:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 15 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (ix) FEATURE:                                                                     (A) NAME/KEY: Other                                                           (B) LOCATION: 2...2                                                 #Residue can be either Gly or Ala                                                       (A) NAME/KEY: Other                                                           (B) LOCATION: 15...15                                               #Residue can be either Pro or Ala                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:15:                                #Ala Pro Gly Ala Xaaro Pro Xaa Gly Pro Pro                                    #                 15                                                          - (2) INFORMATION FOR SEQ ID NO:16:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 15 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:16:                                #Val Ser Thr Leu Sersp Leu Gln Gly Pro Leu                                    #                 15                                                          - (2) INFORMATION FOR SEQ ID NO:17:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 25 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:17:                                #Val Val Thr Phe Ala Serer Gly Arg Tyr Thr                                    #                 15                                                          -  Asp Lys Leu Gly Thr Ser Val Ala Ala                                        #             25                                                              - (2) INFORMATION FOR SEQ ID NO:18:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 25 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (ix) FEATURE:                                                                     (A) NAME/KEY: Other                                                           (B) LOCATION: 15...15                                               #Residue can be either Ala or Arg                                                       (A) NAME/KEY: Other                                                           (B) LOCATION: 23...23                                               #Residue can be either Val or Leu                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:18:                                #Asp Ser Thr Ala Xaa Xaasp Arg Gly Tyr Val                                    #                 15                                                          -  Ala Ser Pro Pro Thr Leu Xaa Val Val                                        #             25                                                              - (2) INFORMATION FOR SEQ ID NO:19:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 8 amino                                                           (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:19:                                -  Glu Pro Glu Gly Val Ala Pro Pro                                              1               5                                                           - (2) INFORMATION FOR SEQ ID NO:20:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 25 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:20:                                #Asp Val Ser Ala Tyr Alaro Ala Gly Phe Pro                                    #                 15                                                          -  Ala Val Asp Pro Xaa Xaa Tyr Val Val                                        #             25                                                              - (2) INFORMATION FOR SEQ ID NO:21:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 15 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:21:                                #Val Gln Gln Val Proro Gly Xaa Ala Ala Tyr                                    #                 15                                                          - (2) INFORMATION FOR SEQ ID NO:22:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 15 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:22:                                #Leu Met Val Pro Serly Leu Pro Val Glu Tyr                                    #                 15                                                          - (2) INFORMATION FOR SEQ ID NO:23:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 19 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:23:                                #Leu Met Val Pro Ser Proeu Pro Val Glu Tyr                                    #                 15                                                          -  Ser Met Gly                                                                - (2) INFORMATION FOR SEQ ID NO:24:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 15 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:24:                                #Leu Asp Val Phe Serly Leu Pro Val Glu Tyr                                    #                 15                                                          - (2) INFORMATION FOR SEQ ID NO:25:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 14 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:25:                                #Met Val Pro Asnly Leu His Arg Leu Arg Met                                    #                 10                                                          - (2) INFORMATION FOR SEQ ID NO:26:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (ix) FEATURE:                                                                     (A) NAME/KEY: Other                                                           (B) LOCATION: 16...16                                               #Residue can be either Ser or Val                                                       (A) NAME/KEY: Other                                                           (B) LOCATION: 17...17                                               #Residue can be either Gln or Val                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:26:                                #Gln Ala Glu Pro Ala Xaaal Gly Ala Ala Ala                                    #                 15                                                          -  Xaa Arg Ile Asp                                                                         20                                                               - (2) INFORMATION FOR SEQ ID NO:27:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 14 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (ix) FEATURE:                                                                     (A) NAME/KEY: Other                                                           (B) LOCATION: 4...4                                                 #Residue can be either Tyr or Pro                                                       (A) NAME/KEY: Other                                                           (B) LOCATION: 8...8                                                 #Residue can be either Val or Gly                                                       (A) NAME/KEY: Other                                                           (B) LOCATION: 9...9                                                 #Residue can be either Ile or Tyr                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:27:                                #Ala Arg Gly Thraa Asp Ile Glu Xaa Xaa Phe                                    #                 10                                                          - (2) INFORMATION FOR SEQ ID NO:28:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 15 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:28:                                #Arg Asp Ala Gly Pheer Val Ser Asp Tyr Ala                                    #                 15                                                          - (2) INFORMATION FOR SEQ ID NO:29:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 16 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (ix) FEATURE:                                                                     (A) NAME/KEY: Other                                                           (B) LOCATION: 2...2                                                 #Residue can be either Leu or Pro                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:29:                                #Thr Val Asp Ala Asp Glnla Xaa Leu Gly Xaa                                    #                 15                                                          - (2) INFORMATION FOR SEQ ID NO:30:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 330 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:30:                                #Val Ala Gly Met Leu Argrg Phe Arg Gly Ala                                    #                 15                                                          #Leu Leu Ser Ala Leu Ilela Met Gly Val Ala                                    #             30                                                              #Phe Ser Arg Pro Gly Leula Pro Ala Glu Ala                                    #         45                                                                  #Ser Met Gly Arg Asp Ileln Val Pro Ser Pro                                    #     60                                                                      #Ser Pro Ala Leu Tyr Leusn Gly Gly Ala Asn                                    # 80                                                                          #Ser Gly Trp Asp Ile Asnla Gln Asp Asp Phe                                    #                 95                                                          #Gly Ile Ser Val Val Metrp Tyr Tyr Gln Ser                                    #            110                                                              #Asp Trp Tyr Ser Pro Alaer Ser Phe Tyr Ser                                    #        125                                                                  #Trp Glu Thr Phe Leu Thrys Gln Thr Tyr Lys                                    #    140                                                                      #Lys Gln Ile Lys Pro Thryr Leu Gln Ser Asn                                    #160                                                                          #Gly Leu Ser Ala Leu Thrly Leu Ser Met Ala                                    #                175                                                          #Tyr Val Gly Ser Met Serro Asp Gln Phe Ile                                    #            190                                                              #Pro Ser Leu Ile Gly Leuer Asn Ala Met Gly                                    #        205                                                                  #Ala Asp Met Trp Gly Proly Gly Tyr Lys Ala                                    #    220                                                                      #Pro Thr Val Asn Val Glyrp Lys Arg Asn Asp                                    #240                                                                          #Met Tyr Cys Gly Asn Glysn Thr Arg Ile Trp                                    #                255                                                          #Pro Ala Lys Leu Leu Gluly Gly Asn Asn Leu                                    #            270                                                              #Gln Asp Gly Tyr Asn Alaer Asn Ile Lys Phe                                    #        285                                                                  #Pro Asp Ser Gly Thr Hisla Val Phe Asn Phe                                    #    300                                                                      #Asp Met Lys Pro Asp Leuly Glu Gln Leu Asn                                    #320                                                                          -  Gln Gln Tyr Leu Gly Ala Thr Pro Gly Ala                                    #                330                                                          - (2) INFORMATION FOR SEQ ID NO:31:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 327 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:31:                                #Trp Gly Arg Trp Leu Leuly Lys Ile Arg Ala                                    #                 15                                                          #Ile Ser Leu Ala Gly Glyhr Leu Pro Ser Leu                                    #             30                                                              #Gly Leu Pro Val Glu Tyrla Phe Ser Arg Pro                                    #         45                                                                  #Thr Ile Lys Val Gln Phelu Ala Met Gly Arg                                    #     60                                                                      #Tyr Leu Leu Asp Gly Leuly Ser Pro Ala Val                                    # 80                                                                          #Ile Asn Thr Ser Ala Pheyr Asn Gly Trp Asp                                    #                 95                                                          #Val Met Pro Val Gly Glyer Gly Leu Ser Val                                    #            110                                                              #Pro Ala Cys Gly Lys Alaer Asp Trp Tyr Ser                                    #        125                                                                  #Leu Thr Ser Glu Leu Proys Trp Glu Thr Phe                                    #    140                                                                      #Ser Thr Gly Ser Ala Valsn Arg Ser Val Lys                                    #160                                                                          #Leu Ile Leu Ala Ala Tyrla Gly Ser Ser Ala                                    #                175                                                          #Leu Ser Ala Leu Met Asple Tyr Ala Gly Ser                                    #            190                                                              #Gly Leu Ala Met Gly Asplu Pro Gln Leu Ile                                    #        205                                                                  #Gly Pro Pro Asn Asp Prola Ala Asp Met Trp                                    #    220                                                                      #Ala Gly Lys Leu Val Alasp Pro Ile Leu Gln                                    #240                                                                          #Asn Gly Thr Pro Ser Glurp Val Tyr Cys Gly                                    #                255                                                          #Leu Glu Asn Phe Val Hisal Pro Ala Glu Phe                                    #            270                                                              #Asn Gly Ala Gly Gly Hishe Gln Asp Ala Tyr                                    #        285                                                                  #Thr His Ser Trp Glu Tyreu Asn Ala Asp Gly                                    #    300                                                                      #Asp Leu Gln Asn Thr Leusn Ala Met Lys Pro                                    #320                                                                          -  Met Ala Val Pro Arg Ser Gly                                                                 325                                                          - (2) INFORMATION FOR SEQ ID NO:32:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 338 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:32:                                #Val Thr Gly Met Ser Argrg Val Arg Gly Ala                                    #                 15                                                          #Leu Val Ser Gly Leu Valla Val Gly Ala Ala                                    #             30                                                              #Ala Phe Ser Arg Pro Glyhr Ala Thr Ala Gly                                    #         45                                                                  #Pro Ser Met Gly Arg Aspeu Gln Val Pro Ser                                    #     60                                                                      #Asn Ser Pro Ala Leu Tyrln Ser Gly Gly Ala                                    # 80                                                                          #Phe Ser Gly Trp Asp Ilerg Ala Gln Asp Asp                                    #                 95                                                          #Ser Gly Leu Ser Val Vallu Trp Tyr Asp Gln                                    #            110                                                              #Ser Asp Trp Tyr Gln Proln Ser Ser Phe Tyr                                    #        125                                                                  #Lys Trp Glu Thr Phe Leuly Cys Gln Thr Tyr                                    #    140                                                                      #Asn Arg His Val Lys Proly Trp Leu Gln Ala                                    #160                                                                          #Ala Ala Ser Ser Ala Leual Gly Leu Ser Met                                    #                175                                                          #Val Tyr Ala Gly Ala Metis Pro Gln Gln Phe                                    #            190                                                              #Gly Pro Thr Leu Ile Glyro Ser Gln Ala Met                                    #        205                                                                  #Ala Ser Asp Met Trp Glyla Gly Gly Tyr Lys                                    #    220                                                                      #Asp Pro Leu Leu Asn Valla Trp Gln Arg Asn                                    #240                                                                          #Trp Val Tyr Cys Gly Asnsn Asn Thr Arg Val                                    #                255                                                          #Leu Pro Ala Lys Phe Leueu Gly Gly Asn Asn                                    #            270                                                              #Phe Gln Asp Ala Tyr Asnhr Ser Asn Ile Lys                                    #        285                                                                  #Phe Pro Asp Ser Gly Thrsn Gly Val Phe Asp                                    #    300                                                                      #Asn Ala Met Lys Pro Asprp Gly Ala Gln Leu                                    #320                                                                          #Thr Gly Pro Ala Pro Glnly Ala Thr Pro Asn                                    #                335                                                          -  Gly Ala                                                                    - (2) INFORMATION FOR SEQ ID NO:33:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 325 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:33:                                #Trp Gly Arg Arg Leu Metrg Lys Ile Arg Ala                                    #                 15                                                          #Gly Leu Val Gly Leu Alala Val Val Leu Pro                                    #             30                                                              #Arg Pro Gly Leu Pro Valla Gly Ala Phe Ser                                    #         45                                                                  #Gly Arg Asp Ile Lys Valro Ser Pro Ser Met                                    #     60                                                                      #Ala Val Tyr Leu Leu Asply Asn Asn Ser Pro                                    # 80                                                                          #Trp Asp Ile Asn Thr Prosp Asp Tyr Asn Gly                                    #                 95                                                          #Ser Ile Val Met Pro Valyr Gln Ser Gly Leu                                    #            110                                                              #Tyr Ser Pro Ala Cys Glyhe Tyr Ser Asp Trp                                    #        125                                                                  #Thr Phe Leu Thr Ser Gluhr Tyr Lys Trp Glu                                    #    140                                                                      #Val Lys Pro Thr Gly Serer Ala Asn Arg Ala                                    #160                                                                          #Ser Ala Met Ile Leu Alaer Met Ala Gly Ser                                    #                175                                                          #Gly Ser Leu Ser Ala Leuln Phe Ile Tyr Ala                                    #            190                                                              #Leu Ile Gly Leu Ala Metly Met Gly Pro Ser                                    #        205                                                                  #Met Trp Gly Pro Ser Seryr Lys Ala Ala Asp                                    #    220                                                                      #Gln Gln Ile Pro Lys Leurg Asn Asp Pro Thr                                    #240                                                                          #Cys Gly Asn Gly Thr Prorg Leu Trp Val Tyr                                    #                255                                                          #Glu Phe Leu Glu Asn Phela Asn Ile Pro Ala                                    #            270                                                              #Ala Tyr Asn Ala Ala Glyeu Lys Phe Gln Asp                                    #        285                                                                  #Asn Gly Thr His Ser Trphe Asn Phe Pro Pro                                    #    300                                                                      #Lys Gly Asp Leu Gln Serln Leu Asn Ala Met                                    #320                                                                          -  Ser Leu Gly Ala Gly                                                                         325                                                          - (2) INFORMATION FOR SEQ ID NO:34:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 338 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:34:                                #Val Thr Gly Met Ser Argrg Val Arg Gly Ala                                    #                 15                                                          #Leu Val Ser Gly Leu Valla Val Gly Ala Ala                                    #             30                                                              #Ala Phe Ser Arg Pro Glyhr Ala Thr Ala Gly                                    #         45                                                                  #Pro Ser Met Gly Arg Aspeu Gln Val Pro Ser                                    #     60                                                                      #Asn Ser Pro Ala Leu Tyrln Ser Gly Gly Ala                                    # 80                                                                          #Phe Ser Gly Trp Asp Ilerg Ala Gln Asp Asp                                    #                 95                                                          #Ser Gly Leu Ser Val Vallu Trp Tyr Asp Gln                                    #            110                                                              #Ser Asp Trp Tyr Gln Proln Ser Ser Phe Tyr                                    #        125                                                                  #Lys Trp Glu Thr Phe Leuly Cys Gln Thr Tyr                                    #    140                                                                      #Asn Arg His Val Lys Proly Trp Leu Gln Ala                                    #160                                                                          #Ala Ala Ser Ser Ala Leual Gly Leu Ser Met                                    #                175                                                          #Val Tyr Ala Gly Ala Metis Pro Gln Gln Phe                                    #            190                                                              #Gly Pro Thr Leu Ile Glyro Ser Gln Ala Met                                    #        205                                                                  #Ala Ser Asp Met Trp Glyla Gly Gly Tyr Lys                                    #    220                                                                      #Asp Pro Leu Leu Asn Valla Trp Gln Arg Asn                                    #240                                                                          #Trp Val Tyr Cys Gly Asnsn Asn Thr Arg Val                                    #                255                                                          #Leu Pro Ala Lys Phe Leueu Gly Gly Asn Asn                                    #            270                                                              #Phe Gln Asp Ala Tyr Asnhr Ser Asn Ile Lys                                    #        285                                                                  #Phe Pro Asp Ser Gly Thrsn Gly Val Phe Asp                                    #    300                                                                      #Asn Ala Met Lys Pro Asprp Gly Ala Gln Leu                                    #320                                                                          #Thr Gly Pro Ala Pro Glnly Ala Thr Pro Asn                                    #                335                                                          -  Gly Ala                                                                    - (2) INFORMATION FOR SEQ ID NO:35:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 323 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:35:                                #Trp Gly Arg Arg Leu Metrg Lys Ile Arg Ala                                    #                 15                                                          #Gly Leu Val Gly Leu Alala Val Val Leu Pro                                    #             30                                                              #Arg Pro Gly Leu Pro Valla Gly Ala Phe Ser                                    #         45                                                                  #Gly Arg Asp Ile Lys Valro Ser Pro Ser Met                                    #     60                                                                      #Ala Val Tyr Leu Leu Asply Asn Asn Ser Pro                                    # 80                                                                          #Trp Asp Ile Asn Thr Prosp Asp Tyr Asn Gly                                    #                 95                                                          #Ser Ile Val Met Pro Valyr Gln Ser Gly Leu                                    #            110                                                              #Tyr Ser Pro Ala Cys Glyhe Tyr Ser Asp Trp                                    #        125                                                                  #Thr Leu Leu Thr Ser Gluhr Tyr Lys Trp Glu                                    #    140                                                                      #Val Lys Pro Thr Gly Serer Ala Asn Arg Ala                                    #160                                                                          #Ser Ala Met Ile Leu Alaer Met Ala Gly Ser                                    #                175                                                          #Gly Ser Leu Ser Ala Leuln Phe Ile Tyr Ala                                    #            190                                                              #Gly Leu Ala Met Gly Asply Met Gly Leu Ile                                    #        205                                                                  #Gly Pro Ser Ser Asp Prola Ala Asp Met Trp                                    #    220                                                                      #Ile Pro Lys Leu Val Alasp Pro Thr Gln Gln                                    #240                                                                          #Asn Gly Thr Pro Asn Glurp Val Tyr Cys Gly                                    #                255                                                          #Leu Glu Asn Phe Val Argle Pro Ala Glu Phe                                    #            270                                                              #Lys Pro Ala Gly Gly Hishe Gln Asp Ala Tyr                                    #        285                                                                  #Thr His Ser Trp Glu Tyrhe Pro Pro Asn Gly                                    #    300                                                                      #Asp Leu Gln Ser Ser Leusn Ala Met Lys Gly                                    #320                                                                          -  Gly Ala Gly                                                                - (2) INFORMATION FOR SEQ ID NO:36:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 333 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:36:                                #Phe Gly Leu Ala Ala Lysln Met Arg Lys Leu                                    #                 15                                                          #Gly Thr Ala Leu Leu Alahr Ile Ala Val Ile                                    #             30                                                              #Ile Ala Val Ala Phe Seral Gly Asp Thr Ala                                    #         45                                                                  #Val Pro Ser Pro Ser Metal Glu Tyr Leu Gln                                    #     60                                                                      #Gly Gly Gln His Ala Valle Gln Phe Gln Gly                                    # 80                                                                          #Asp Tyr Asn Gly Trp Aspeu Arg Ala Gln Glu                                    #                 95                                                          #His Ser Gly Leu Ser Valhe Glu Glu Tyr Tyr                                    #            110                                                              #Tyr Ser Asn Trp Tyr Glnly Gln Ser Ser Phe                                    #        125                                                                  #Tyr Lys Trp Glu Thr Phely Gln His Tyr Thr                                    #    140                                                                      #Ala Asn Lys Asn Val Leuro Ser Trp Leu Gln                                    #160                                                                          #Met Ser Gly Ser Ser Alala Val Gly Leu Ser                                    #                175                                                          #Phe Pro Tyr Ala Ala Seryr Tyr Pro Gln Gln                                    #            190                                                              #Trp Trp Pro Thr Met Ilesn Pro Ser Glu Gly                                    #        205                                                                  #Asn Ala Asn Ser Met Trpsp Ser Gly Gly Tyr                                    #    220                                                                      #Asn Asp Pro Met Val Glnro Ala Trp Lys Arg                                    #240                                                                          #Ile Trp Val Tyr Cys Glyla Asn Asn Thr Arg                                    #                255                                                          #Asn Ile Pro Ala Lys Phelu Leu Gly Gly Asp                                    #            270                                                              #Ile Phe Gln Asn Thr Tyreu Ser Thr Asn Glu                                    #        285                                                                  #Asn Phe Pro Pro Asn Glyrg Asn Gly Val Phe                                    #    300                                                                      #Leu Val Ala Met Lys Proyr Trp Asn Gln Gln                                    #320                                                                          #Asn Asn Alaln Gln Ile Leu Asn Gly Ser Asn                                    #                330                                                          - (2) INFORMATION FOR SEQ ID NO:37:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 340 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:37:                                #Arg Ser Ala Ala Thr Thrln Val Arg Arg Leu                                    #                 15                                                          #Gly Ala Val Leu Val Tyrla Ile Ala Ala Met                                    #             30                                                              #Thr Ala Gly Ala Phe Serhe Gly Gly Pro Ala                                    #         45                                                                  #Val Pro Ser Ala Ser Metal Glu Tyr Leu Gln                                    #     60                                                                      #Gly Gly Pro His Ala Valal Gln Phe Gln Gly                                    # 80                                                                          #Asp Tyr Asn Gly Trp Aspeu Arg Ala Gln Asp                                    #                 95                                                          #Gln Ser Gly Leu Ser Valhe Glu Glu Tyr Tyr                                    #            110                                                              #Tyr Thr Asp Trp Tyr Glnly Gln Ser Ser Phe                                    #        125                                                                  #Tyr Lys Trp Glu Thr Phely Gln Asn Tyr Thr                                    #    140                                                                      #Ala Asn Lys Gly Val Serro Ala Trp Leu Gln                                    #160                                                                          #Met Ser Gly Gly Ser Alala Val Gly Leu Ser                                    #                175                                                          #Phe Pro Tyr Ala Ala Seryr Tyr Pro Gln Gln                                    #            190                                                              #Trp Trp Pro Thr Leu Ilesn Pro Ser Glu Gly                                    #        205                                                                  #Asn Ala Asn Ser Met Trpsp Ser Gly Gly Tyr                                    #    220                                                                      #Asn Asp Pro Met Val Glnro Ala Trp Lys Arg                                    #240                                                                          #Ile Trp Val Tyr Cys Glyla Asn Asn Thr Arg                                    #                255                                                          #Asn Ile Pro Ala Lys Phesp Leu Gly Gly Asp                                    #            270                                                              #Thr Phe Arg Asp Thr Tyreu Arg Thr Asn Gln                                    #        285                                                                  #Asn Phe Pro Pro Asn Glyrg Asn Gly Val Phe                                    #    300                                                                      #Leu Val Ala Met Lys Alayr Trp Asn Glu Gln                                    #320                                                                          #Pro Pro Ala Ala Pro Alaeu Asn Gly Ala Thr                                    #                335                                                          -  Ala Pro Ala Ala                                                                         340                                                              - (2) INFORMATION FOR SEQ ID NO:38:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 20 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Other                                               -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:38:                                # 20               AACAC                                                      - (2) INFORMATION FOR SEQ ID NO:39:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 20 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Other                                               -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:39:                                # 20               TTGGC                                                      - (2) INFORMATION FOR SEQ ID NO:40:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 1211 base                                                         (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Genomic DNA                                         -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:40:                                #TGGGCCTTGG    60GGAGGAT TGACGGTATG AGACTTCTTG ACAGGATTCG                     #GGTGGGCCTG   120GCGTCGT GGCTGTCGCG ACAGCGATGA TGCCTGCTTT                     #GGAGTACCTG   180CGACCGC CGGAGCATTC TCCCGGCCAG GTCTGCCGGT                     #CGGTGGCGAG   240CGTCGAT GGGGCGCGAC ATCAAGATCC AGTTCCAGAG                     #CAACGGCTGG   300TCTACCT GCTCGACGGC CTGCGTGCGC AGGAGGACTT                     #GGTGATGCCG   360AGGCTTT CGAGTGGTTC CTCGACAGCG GCATCTCCGT                     #CAAGGGCCCG   420CCAGCTT CTACACCGAC TGGTACGCCC CCGCCCGTAA                     #GCTGCAGGCC   480AGTGGGA GACCTTCCTG ACCCAGGAGC TCCCGGGCTG                     #GGGTTCGGCC   540AGCCGAC CGGCAGCGGC CCTGTCGGTC TGTCGATGGC                     #GATGTCCGGC   600CGACCTG GCACCCGGAG CAGTTCATCT ACGCGGGCTC                     #GGGTGACGCC   660CCGAGGG CTGGTGGCCG TTCCTGATCA ACATCTCGAT                     #AGCGGTTGGA   720CCGACGA CATGTGGGGC AAGACCGAGG GGATCCCAAC                     #CCGTATCTGG   780CGATGCT GAACATCCCG ACCCTGGTCG CCAACAACAC                     #CGCCACGTTC   840ACGGCCA GCCCACCGAG CTCGGCGGCG GCGACCTGCC                     #CGCCGCGGGT   900CCATCCG CACCAACGAG ACCTTCCGCG ACAACTACAT                     #GTACTGGGGT   960TGTTCAA CTTCCCGGCC AACGGCACGC ACAACTGGGC                     #GTTGCACGAA  1020CGATGAA GCCTGACCTG CAGGCGCACC TTCTCTGACG                     #GTGGCCGACA  1080CCGATTG CGGCCGAGGG TTTCGTCGTC CGGGGCTACT                     #TGCGCTACGA  1140CGCGATG GTGGCTCATC AGGAACGCCG AGGGGGTCAT                     #CGTCGAGTAC  1200AGCAATC CTTCCTGCCC GACGGAGAGG TCAACATCCA                     #     1211                                                                    - (2) INFORMATION FOR SEQ ID NO:41:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 485 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Genomic DNA                                         -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:41:                                #TCTCGCGGTG    60TCAACAC CGCCGCCTTC GAGTGGTACG TCGACTCGGG                     #GGCCTGCGGT   120GCGGGCA GTCCAGCTTC TACAGCGACT GGTACAGCCC                     #GCCGGCCTAC   180AGACCTA CAAGTGGGAG ACGTTCCTGA CCCAGGAGCT                     #GTCCATGGCC   240AGGGGGT CGACCCGAAC CGCAACGCGG CCGTCGGTCT                     #CGCCGGGTCG   300TGACGCT GGCGATCTAC CACCCGCAGC AGTTCCAGTA                     #CATCTCGATG   360TGAACCC GTCCGAGGGG TGGTGGCCGA TGCTGATCAA                     #CCCGAGCAGC   420GCTACAA GGCCAACGAC ATGTGGGGTC CACCGAAGGA                     #CAACACCCCC   480ACGACCC GATGGTCAAC ATCGGCAAGC TGGTGGCCAA                     #           485                                                               - (2) INFORMATION FOR SEQ ID NO:42:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 1052 base                                                         (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Genomic DNA                                         -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:42:                                #GCGGGGCTCC    60GTGGGTT GTTTGCCGTT ATGAAGTTCA CAGAGAAGTG                     #GCTGCCCGGA   120TGCACCG GGTGGGCGTT GCCGATATGG CCGCCGTTGC                     #CGGTCTTCCT   180CCGGGGG TTCGGCAACG GCCGGGGCAT TCTCCCGGCC                     #CCAGTTCCAG   240ACGTGTT CTCGCCGTCG ATGGGCCGCG ACATCCGGGT                     #CGACTACAAC   300ATGCGGT CTACCTGCTC GACGGTCTGC GTGCCCAGGA                     #GTCGACGATC   360ACACCCC TGCGTTCGAG TGGTTCTACG AGTCCGGCTT                     #TCGGGGCAAC   420GACAGTC CAGCTTCTAC AGCGACTGGT ACCAGCCGTC                     #GACGTGGCTG   480CCTACAA GTGGGAGACG TTCCTGACCC AGGAGCTGCC                     #GATGGCGGGC   540GAGTGTC GCGCACCGGC AACGCGTTCG TCGGCCTGTC                     #CTCGTCGCTG   600CCTACGC GATCCATCAC CCGCAGCAGT TCATCTACGC                     #GGCGATGAAC   660ACCCGTC CGAGGGCTGG TGGCCGATGC TGATCGGGCT                     #GGCGTGGAAG   720TCAACGC CGAGAGCATG TGGGGCCCGT CCTCGGACCC                     #GATCTGGATC   780TGGTCAA CATCAACCAG CTGGTGGCCA ACAACACCCG                     #GAACCTGATG   840GCACCCC GTCGGAGCTG GACACCGGGA CCCCGGGCCA                     #TGACAACTAC   900TCGAAGG ATTCACGTTG CGGACCAACA TCGCCTTCCG                     #CCACAGCTGG   960GCACCAA CGGTGTCTTC AACTTCCCGG CCTCGGGCAC                     #TCTGGGAGCT  1020AGCAGCT GCAGCAGATG AAGCCCGACA TCCAGCGGGT                     #        1052      CCACC CACCCCACAC CC                                        - (2) INFORMATION FOR SEQ ID NO:43:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 326 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:43:                                #Trp Ala Arg Arg Phe Glyrg Ile Arg Gly Pro                                    #                 15                                                          #Ala Leu Val Gly Leu Alahr Ala Met Met Pro                                    #             30                                                              #Arg Pro Gly Leu Pro Valla Gly Ala Phe Ser                                    #         45                                                                  #Gly Arg Asp Ile Lys Ilero Ser Pro Ser Met                                    #     60                                                                      #Ala Leu Tyr Leu Leu Asply Glu Asn Ser Pro                                    # 80                                                                          #Trp Asp Ile Asn Thr Glnlu Asp Phe Asn Gly                                    #                 95                                                          #Ser Val Val Met Pro Valeu Asp Ser Gly Ile                                    #            110                                                              #Tyr Ala Pro Ala Arg Asnhe Tyr Thr Asp Trp                                    #        125                                                                  #Thr Phe Leu Thr Gln Gluhr Tyr Lys Trp Glu                                    #    140                                                                      #Val Lys Pro Thr Gly Serln Ala Asn Arg Ala                                    #160                                                                          #Ala Ala Leu Asn Leu Alaer Met Ala Gly Ser                                    #                175                                                          #Gly Ser Met Ser Gly Pheln Phe Ile Tyr Ala                                    #            190                                                              #Leu Ile Asn Ile Ser Metly Trp Trp Pro Phe                                    #        205                                                                  #Met Trp Gly Lys Thr Gluhe Lys Ala Asp Asp                                    #    220                                                                      #Asp Pro Met Leu Asn Ileal Gly Gln Arg Asn                                    #240                                                                          #Trp Val Tyr Cys Gly Asnsn Asn Thr Arg Ile                                    #                255                                                          #Leu Pro Ala Thr Phe Leueu Gly Gly Gly Asp                                    #            270                                                              #Phe Arg Asp Asn Tyr Ilerg Thr Asn Glu Thr                                    #        285                                                                  #Phe Pro Ala Asn Gly Thrsn Gly Val Phe Asn                                    #    300                                                                      #Gln Ala Met Lys Pro Asprp Gly Arg Glu Leu                                    #320                                                                          -  Leu Gln Ala His Leu Leu                                                                     325                                                          - (2) INFORMATION FOR SEQ ID NO:44:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 161 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:44:                                #Glu Trp Tyr Val Asp Sersn Thr Ala Ala Phe                                    #                 15                                                          #Gln Ser Ser Phe Tyr Seret Pro Val Gly Gly                                    #             30                                                              #Gly Cys Gln Thr Tyr Lysla Cys Gly Lys Ala                                    #         45                                                                  #Ala Tyr Leu Ala Ala Asnhr Gln Glu Leu Pro                                    #     60                                                                      #Val Gly Leu Ser Met Alasn Arg Asn Ala Ala                                    # 80                                                                          #His Pro Gln Gln Phe Glnhr Leu Ala Ile Tyr                                    #                 95                                                          #Pro Ser Glu Gly Trp Trper Gly Tyr Leu Asn                                    #            110                                                              #Ala Gly Gly Tyr Lys Alale Ser Met Gly Asp                                    #        125                                                                  #Ser Ser Ala Trp Lys Argro Pro Lys Asp Pro                                    #    140                                                                      #Val Ala Asn Asn Thr Prosn Ile Gly Lys Leu                                    #160                                                                          -  Leu                                                                        - (2) INFORMATION FOR SEQ ID NO:45:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 334 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:45:                                #Ala Lys Ala Ala Met Hisys Trp Arg Gly Ser                                    #                 15                                                          #Ala Leu Pro Gly Leu Ilesp Met Ala Ala Val                                    #             30                                                              #Ala Phe Ser Arg Pro Glyer Ala Thr Ala Gly                                    #         45                                                                  #Pro Ser Met Gly Arg Aspeu Asp Val Phe Ser                                    #     60                                                                      #His Ala Val Tyr Leu Leuln Gly Gly Gly Thr                                    # 80                                                                          #Gly Trp Asp Ile Asn Thrln Asp Asp Tyr Asn                                    #                 95                                                          #Leu Ser Thr Ile Met Prohe Tyr Glu Ser Gly                                    #            110                                                              #Trp Tyr Gln Pro Ser Arger Phe Tyr Ser Asp                                    #        125                                                                  #Glu Thr Phe Leu Thr Glnyr Thr Tyr Lys Trp                                    #    140                                                                      #Gly Val Ser Arg Thr Glyeu Glu Ala Asn Arg                                    #160                                                                          #Ser Ala Ala Leu Thr Tyreu Ser Met Ala Gly                                    #                175                                                          #Ala Ser Ser Leu Ser Glyln Gln Phe Ile Tyr                                    #            190                                                              #Met Leu Ile Gly Leu Alalu Gly Trp Trp Pro                                    #        205                                                                  #Ser Met Trp Gly Pro Serly Phe Asn Ala Glu                                    #    220                                                                      #Met Val Asn Ile Asn Glnys Arg Asn Asp Pro                                    #240                                                                          #Tyr Cys Gly Thr Gly Thrhr Arg Ile Trp Ile                                    #                255                                                          #Gln Asn Leu Met Ala Alahr Gly Thr Pro Gly                                    #            270                                                              #Asn Ile Ala Phe Arg Asphe Thr Leu Arg Thr                                    #        285                                                                  #Val Phe Asn Phe Pro Alaly Gly Thr Asn Gly                                    #    300                                                                      #Gln Gln Leu Gln Gln Metrp Gly Tyr Trp Gly                                    #320                                                                          #Gln Ala Thr Alale Gln Arg Val Leu Gly Ala                                    #                330                                                          - (2) INFORMATION FOR SEQ ID NO:46:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 795 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Genomic DNA                                         -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:46:                                #GGGTAACGAT    60GCCATCT CTTGGGTCCT GGGTCGGGAG GCCATGTTCT                     #AGGAGCGGCG   120GCGATGT GACCAACATG CGAACAGCGA CAACGAAGCT                     #GGCGAACGCC   180CATTGGT GGCCGCCACG GGGATGGTCA GCGCGGCGAC                     #GTTCGACCTG   240AGGTCCG TTACACGCTC ACCTCGGCCG GCGCTTACGA                     #GTATGCGTTC   300CGCAGCC GCCGAGCATG CAGGCGTTCA ACGCCGACGC                     #AACCACGATG   360AGGTCAG CCTCGCCCCG GGTGTGCCGT GGGTCTTCGA                     #GCAGGCCGCC   420GGGCGAT CCTTCAGGTC AGCAGCACCA CCCGCGGTGG                     #GCACGACGAC   480GCGACAT CGCCGTCGAT GGCCAGGAGG TGCTCAGCCA                     #AGTCCGGCCA   540GGTGCCA GCTCGGTCAG TGGTGAGTCA CCTCGCCGAG                     #CGGGTCAGCG   600CGGCTCG CGGTGCAGCA CCCCGAGGCG CTGGGTCGCG                     #GGGTAGACCA   660GCTGGCC CCGCGCGGCC CCTCGGCGAG GATCTGCTCC                     #CCCGGGACAC   720TAACTCC AGACCCTTGG TCTGCGTGGG TGCCACCGCG                     #ACGAAATCGT   780CACCACG CTGGTGCCCT CCCGGTCCGC CTCCGCACGC                     #   795                                                                       - (2) INFORMATION FOR SEQ ID NO:47:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 142 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:47:                                #Ala Leu Gly Ala Ala Alahr Lys Leu Gly Ala                                    #                 15                                                          #Ala Thr Ala Asn Ala Glnly Met Val Ser Ala                                    #             30                                                              #Ser Ala Gly Ala Tyr Glurg Tyr Thr Leu Thr                                    #         45                                                                  #Pro Ser Met Gln Ala Pheeu Thr Thr Gln Pro                                    #     60                                                                      #Glu Lys Val Ser Leu Alala Phe Ala Lys Arg                                    # 80                                                                          #Met Ala Asp Pro Asn Trpal Phe Glu Thr Thr                                    #                 95                                                          #Gly Gly Gln Ala Ala Proer Ser Thr Thr Arg                                    #            110                                                              #Gln Glu Val Leu Ser Glnle Ala Val Asp Gly                                    #        125                                                                  #Leu Gly Gln Trpro Tyr Asn Val Arg Cys Gln                                    #    140                                                                      - (2) INFORMATION FOR SEQ ID NO:48:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 300 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Genomic DNA                                         -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:48:                                #CTGCGCTTGC    60CGGTTTT CATCGATGCC GCACACAACC CCGGTGGGCC                     #GGTGATGGGG   120ACGAGTT CGACTTCCGG TATCTCGTCG GCGTCGTCTC                     #CGGTCTCGCA   180ACGGGAT CCGCCAGGAC CCGGGCGTGC CGGACGGGCG                     #CCAGATCGCC   240GCGACAA CCTTCGAAAG GGTGCGGCGC TCAACACGAT                     #CCGATAATCG   300CCCAGTT GTAAGTGTTC CGCCGAAATT GCATTCCACG                     - (2) INFORMATION FOR SEQ ID NO:49:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 563 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Genomic DNA                                         -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:49:                                #CGGCTACGAG    60GCTCAAG AGTCCGCGCC GAGGTGGATG TGACGCTGGA                     #CGACTGGTAT   120GCGAGGC GCTGTACCAC TTCGCCTGGG ACGAGTTCTG                     #CGTGTTGGCC   180AAGTGCA ACTGGGTGAA GGTTTCTCGC ACACCACGGC                     #CACCGAGGTG   240TGCTGCT CAAGCTTCTG CACCCGGTCA TGCCGTTCGT                     #TGTGGAGTCA   300TGACCGG GCGGGCCGGC GCGAGCGAAC GTCTGGGAAA                     #TGCCGCACAA   360ACTGGCC CACGCCCACC GGATACGCGC TGGATCAGGC                     #CGATCAGGGT   420CCCAGAA GTTGATCACC GAGGTGCGCC GGTTCCGCAG                     #GGGTCTGGAC   480AGCGGGT GCCTGCCCGG TTGTCCGGCA TCGACACCGC                     #AGGGCTTCAC   540CGGTGCG CGCGCTGGCC TGGCTTGACC GAGGGTGATG                     #               563CGAGG TGC                                                  - (2) INFORMATION FOR SEQ ID NO:50:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 434 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Genomic DNA                                         -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:50:                                #CGCGGCTTTC    60GGATGAG CAAGTTCGAA GTCGTCACCG GGATGGCGTT                     #CTGGGACGCG   120TCGACGT CGCCGTCGTC GAGGTCGGGC TCGGTGGTCG                     #CCACACCGAC   180ACGCACC GGTCGCGGTC ATCACCCCGA TCGGGGTGGA                     #TCACCCGCCA   240CGATCGC CGAGATCGCC GGGGAGAAGG CCGGAAATCA                     #TCCCGAGGCC   300TGCCGAC CGACACCGTC GCCGTGCTGG CGCGGCAGGT                     #CGAGGATTCG   360TGGCCCA GGCGGTGCGC TCGGATGCGG CTGTAGCGCG                     #TTGCAGGGGC   420TGGGCCG TCAGGTCGCC ATCGGCGGCA GCTGCTCCGG                     #    434                                                                      - (2) INFORMATION FOR SEQ ID NO:51:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 438 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Genomic DNA                                         -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:51:                                #TGCTGATCGA    60GCGCCGG CGGCGGCCAG CTGGTACGGC CATTCCAGCG                     #CGCCCTCACG   120CGCGTGC TGGCCGACCC GGTGTGGAGC AACAGATGTT                     #TTCCCGCCGT   180CAGCGCA TGCACGACGT CCCGGTGCCG CTGGAGGCGC                     #CCATCGTCGC   240ATCGCCA ACGACCACTA CGACCACCTC GACATCGACA                     #CACACCTGCG   300CAGCGGG CCCCGTTCGT GGTGCCGTTG GGCATCGGCG                     #CCCACCGCAT   360CCCGAGG CGCGGATCGT CGAGTTGGAC TGGCACGAAG                     #TGTTCTCCCG   420CTGGTCT GCACCCCCGC CCGGCACTTC TCCGGCCGGT                     # 438              GGC                                                        - (2) INFORMATION FOR SEQ ID NO:52:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 87 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:52:                                #Ala His Asn Pro Gly Glyal Phe Ile Asp Ala                                    #                 15                                                          #Phe Asp Phe Arg Tyr Leurg Leu Arg Asp Glu                                    #             30                                                              #Asp Val Asp Gly Ile Argal Met Gly Asp Lys                                    #         45                                                                  #Leu Ala Leu Phe Val Serro Asp Gly Arg Gly                                    #     60                                                                      #Asn Thr Ile Gln Ile Alays Gly Ala Ala Leu                                    # 80                                                                          -  Glu Leu Leu Ala Ala Gln Leu                                                                 85                                                           - (2) INFORMATION FOR SEQ ID NO:53:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 175 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:53:                                #Glu Val Asp Val Thr Leuer Arg Val Arg Ala                                    #                 15                                                          #Ala Leu Tyr His Phe Alaer Arg Ala Cys Glu                                    #             30                                                              #Leu Ala Lys Val Gln Leusp Trp Tyr Val Glu                                    #         45                                                                  #Leu Ala Thr Val Leu Aspis Thr Thr Ala Val                                    #     60                                                                      #Pro Phe Val Thr Glu Valeu His Pro Val Met                                    # 80                                                                          #Ala Ser Glu Arg Leu Glyhr Gly Arg Ala Gly                                    #                 95                                                          #Pro Thr Pro Thr Gly Tyral Val Ala Asp Trp                                    #            110                                                              #Ala Asp Thr Gln Lys Leula Ala Gln Arg Ile                                    #        125                                                                  #Gln Gly Leu Ala Asp Argrg Phe Arg Ser Asp                                    #    140                                                                      #Asp Thr Ala Gly Leu Asprg Leu Ser Gly Ile                                    #160                                                                          #Trp Leu Asp Arg Glyla Val Arg Ala Leu Ala                                    #                175                                                          - (2) INFORMATION FOR SEQ ID NO:54:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 144 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:54:                                #Val Val Thr Gly Met Alasn Ser Lys Phe Glu                                    #                 15                                                          #Val Ala Val Val Glu Valsp Ala Pro Ile Asp                                    #             30                                                              #Val Val Asn Ala Pro Valrp Asp Ala Thr Asn                                    #         45                                                                  #Thr Asp Tyr Leu Gly Asple Gly Val Asp His                                    #     60                                                                      #Gly Asn His His Pro Prola Gly Glu Lys Ala                                    # 80                                                                          #Ala Val Leu Ala Arg Glnro Thr Asp Thr Val                                    #                 95                                                          #Gln Ala Val Arg Ser Asplu Val Leu Leu Ala                                    #            110                                                              #Ala Val Leu Gly Arg Glnlu Asp Ser Glu Cys                                    #        125                                                                  #Arg Gly Ser Val Ala Serer Cys Ser Gly Cys                                    #    140                                                                      - (2) INFORMATION FOR SEQ ID NO:55:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 145 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:55:                                #Trp Tyr Gly His Ser Serro Ala Ala Ala Ser                                    #                 15                                                          #Leu Ala Asp Pro Val Trpsp Gly Tyr Arg Val                                    #             30                                                              #Gly Pro Gln Arg Met Hisro Ser Arg Ala Val                                    #         45                                                                  #Ala Val Asp Ala Val Valeu Glu Ala Leu Pro                                    #     60                                                                      #Ile Asp Thr Ile Val Alayr Asp His Leu Asp                                    # 80                                                                          #Val Pro Leu Gly Ile Glyrg Ala Pro Phe Val                                    #                 95                                                          #Ala Arg Ile Val Glu Leurp Gly Val Pro Glu                                    #            110                                                              #Leu Thr Leu Val Cys Thris Arg Ile Asp Asp                                    #        125                                                                  #Ser Arg Asp Ser Thr Leuer Gly Arg Leu Phe                                    #    140                                                                      -  Trp                                                                         145                                                                          - (2) INFORMATION FOR SEQ ID NO:56:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 10 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (ix) FEATURE:                                                                     (A) NAME/KEY: Other                                                           (B) LOCATION: 1...1                                                 #Residue can be either Gly, Ile, Leu or                                                      Val                                                                      (A) NAME/KEY: Other                                                           (B) LOCATION: 2...2                                                 #Residue can be either Ile, Leu, Gly or                                                      Ala                                                            -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:56:                                -  Xaa Xaa Ala Pro Xaa Gly Asp Ala Xaa Arg                                    #                 10                                                          - (2) INFORMATION FOR SEQ ID NO:57:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 8 amino                                                           (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (ix) FEATURE:                                                                     (A) NAME/KEY: Other                                                           (B) LOCATION: 7...7                                                 #Residue can be either Ile or Leu                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:57:                                -  Pro Glu Ala Glu Ala Asn Xaa Arg                                              1               5                                                           - (2) INFORMATION FOR SEQ ID NO:58:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 11 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (ix) FEATURE:                                                                     (A) NAME/KEY: Other                                                           (B) LOCATION: 4...4                                                 #Residue can be either Gln or Gly                                                       (A) NAME/KEY: Other                                                           (B) LOCATION: 5...5                                                 #Residue cn be either Gly or Gln                                              -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:58:                                #Arghr Ala Asn Xaa Xaa Glu Tyr Tyr Asp Asn                                    #                 10                                                          - (2) INFORMATION FOR SEQ ID NO:59:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 34 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:59:                                #Leu Arg Gly Tyr Phe Thrlu Ala Glu Ala Asn                                    #                 15                                                          #Gly Ile Leu Ala Pro Ileyr Tyr Asp Leu Arg                                    #             30                                                              -  Gly Asp                                                                    - (2) INFORMATION FOR SEQ ID NO:60:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 20 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Other                                               -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:60:                                # 20               TGCGC                                                      - (2) INFORMATION FOR SEQ ID NO:61:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 20 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Other                                               -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:61:                                # 20               TGGTA                                                      - (2) INFORMATION FOR SEQ ID NO:62:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 313 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Genomic DNA                                         -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:62:                                #CGGCCTCGGT    60GGCTGCG CGGAATACGC GGCAGCCAAT CCCACTGGGC                     #AGTTGACAAC   120CAGGACC CGGTCGCGGT GGCGGCCTCG AACAATCCGG                     #GACACCCTCA   180ACTGTCG GGCCAGCTCA ATCCGCAAGT AAACCTGGTG                     #CTGCCGGCAT   240CACGGTG TTCGCACCGA CCAACGCGGC ATTTAGCAAG                     #ACCTACCACG   300GCTCAAG ACCAATTCGT CACTGCTGAC CAGCATCCTG                     #     313                                                                     - (2) INFORMATION FOR SEQ ID NO:63:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 18 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:63:                                #Glu Arg Leu His Thr Leueu Pro Xaa Tyr Asn                                    #                 15                                                          -  Xaa Gln                                                                    - (2) INFORMATION FOR SEQ ID NO:64:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 25 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:64:                                #Gly Gln Gly Arg Thr Leueu Ser Leu Val Asp                                    #                 15                                                          -  Thr Val Gln Gln Xaa Asp Thr Phe Leu                                        #             25                                                              - (2) INFORMATION FOR SEQ ID NO:65:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 26 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:65:                                #Ala Arg Gly Thr Gly Alale Glu Val Glu Phe                                    #                 15                                                          -  Glu Pro Gly Leu Xaa Xaa Val Xaa Asp Ala                                    #             25                                                              - (2) INFORMATION FOR SEQ ID NO:66:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 32 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Other                                               -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:66:                                #          32      TCCCG GCCAGGTCTG CC                                        - (2) INFORMATION FOR SEQ ID NO:67:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 32 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Other                                               -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:67:                                #          32      CTCTT CCACGCGGAC GT                                        - (2) INFORMATION FOR SEQ ID NO:68:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 30 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Other                                               -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:68:                                #           30     CCGGC CCGGTCTTCC                                           - (2) INFORMATION FOR SEQ ID NO:69:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 26 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Other                                               -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:69:                                #              26  GTGGC CTGAGC                                               - (2) INFORMATION FOR SEQ ID NO:70:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 161 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:70:                                #Glu Trp Tyr Val Asp Sersn Thr Ala Ala Phe                                    #                 15                                                          #Gln Ser Ser Phe Tyr Seret Pro Val Gly Gly                                    #             30                                                              #Gly Cys Gln Thr Tyr Lysla Cys Gly Lys Ala                                    #         45                                                                  #Ala Tyr Leu Ala Ala Asnhr Gln Glu Leu Pro                                    #     60                                                                      #Val Gly Leu Ser Met Alasn Arg Asn Ala Ala                                    # 80                                                                          #His Pro Gln Gln Phe Glnhr Leu Ala Ile Tyr                                    #                 95                                                          #Pro Ser Glu Gly Trp Trper Gly Tyr Leu Asn                                    #            110                                                              #Ala Gly Gly Tyr Lys Alale Ser Met Gly Asp                                    #        125                                                                  #Ser Ser Ala Trp Lys Argrg Thr Glu Asp Pro                                    #    140                                                                      #Val Ala Asn Asn Thr Prosn Ile Gly Lys Leu                                    #160                                                                          -  Leu                                                                        - (2) INFORMATION FOR SEQ ID NO:71:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 33 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Other                                               -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:71:                                #         33       GCCCA GGAAGGGCAC CAG                                       - (2) INFORMATION FOR SEQ ID NO:72:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 32 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Other                                               -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:72:                                #          32      CTCAC CACTGACCGA GC                                        - (2) INFORMATION FOR SEQ ID NO:73:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 20 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Other                                               -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:73:                                # 20               GARCC                                                      - (2) INFORMATION FOR SEQ ID NO:74:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 825 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Genomic DNA                                         -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:74:                                #CGTGCTGATC    60CCGCGCC GGCGGCGGCC AGCTGGTACG GCCATTCCAG                     #TTCGCCCTCA   120ACCGCGT GCTGGCCGAC CCGGTGTGGA GCAACAGATG                     #GCTTCCCGCC   180CGCAGCG CATGCACGAC GTCCCGGTGC CGCTGGAGGC                     #CACCATCGTC   240TGATCAG CCACGACCAC TACGACCACC TCGACATCGA                     #CGCACACCTG   300CCCAGCG GGCCCCGTTC GTGGTGCCGT TGGGCATCGG                     #AGCCCACCGC   360TCCCCGA GGCGCGGATC GTCGAGTTGG ACTGGCACGA                     #GTTGTTCTCC   420CGCTGGT CTGCACCCCC GCCCGGCACT TCTCCGGACG                     #GGCGTTCTTC   480TGTGGGC GTCGTGGGTG GTCACCGGCT CGTCGCACAA                     #CGGTCCGTTC   540GATACAC GAAGAGCTTC GCCGAGATCG GCGACGAGTA                     #CCACATGAAC   600TGCCGAT CGGGGCCTAC CATCCCGCGT TCGCCGACAT                     #CCTGATGGTG   660TGCGCGC CCATCTGGAC CTGACCGAGG TGGACAACAG                     #CGCCGAACGC   720CGACATT CCGCCTCGCC CCGCATCCGT GGTCCGAGCC                     #CGGTCAGCGG   780CCGACGC CGAGCGGGTA CGCCTGACCG TGCCGATTCC                     #                 825GTT CGACCCGTGG TGGCGGTTCT GAACC                          - (2) INFORMATION FOR SEQ ID NO:75:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 273 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:75:                                #Ser Trp Tyr Gly His Serla Pro Ala Ala Ala                                    #                 15                                                          #Val Leu Ala Asp Pro Valal Asp Gly Tyr Arg                                    #             30                                                              #Val Gly Pro Gln Arg Meter Pro Ser Arg Ala                                    #         45                                                                  #Pro Ala Val Asp Ala Valro Leu Glu Ala Leu                                    #     60                                                                      #Asp Ile Asp Thr Ile Valis Tyr Asp His Leu                                    # 80                                                                          #Val Val Pro Leu Gly Ileln Arg Ala Pro Phe                                    #                 95                                                          #Glu Ala Arg Ile Val Gluys Trp Gly Val Pro                                    #            110                                                              #Asp Leu Thr Leu Val Cysla His Arg Ile Asp                                    #        125                                                                  #Phe Ser Arg Asp Ser Thrhe Ser Gly Arg Leu                                    #    140                                                                      #Ser His Lys Ala Phe Pheal Val Thr Gly Ser                                    #160                                                                          #Ala Glu Ile Gly Asp Gluyr Thr Lys Ser Phe                                    #                175                                                          #Ile Gly Ala Tyr His Proeu Thr Leu Leu Pro                                    #            190                                                              #Glu Ala Val Arg Ala Hisis Met Asn Pro Glu                                    #        205                                                                  #Met Val Pro Ile His Trpal Asp Asn Ser Leu                                    #    220                                                                      #Ser Glu Pro Ala Glu Argla Pro His Pro Trp                                    #240                                                                          #Arg Leu Thr Val Pro Ilesp Ala Glu Arg Val                                    #                255                                                          #Phe Asp Pro Trp Trp Argsp Pro Glu Ser Thr                                    #            270                                                              -  Phe                                                                        - (2) INFORMATION FOR SEQ ID NO:76:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 10 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:76:                                -  Ala Lys Thr Ile Ala Tyr Asp Glu Glu Ala                                    #                 10                                                          - (2) INFORMATION FOR SEQ ID NO:77:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 337 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Genomic DNA                                         -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:77:                                #GCTCCCGCTG    60TGCTGGT CAGCTCCAAG GTGTCGACCG TCAAGGATCT                     #CGTCGAGGGC   120TCCAGGC CGGCAAGCCG CTGCTGATCA TCGCCGAGGA                     #CGTCGCCGTC   180CGCTGGT GGTCAACAAG ATCCGCGGCA CCTTCAAGTC                     #CATCCTCACC   240TCGGTGA CCGCCGCAAG GCGATGCTGC AGGACATGGC                     #CGTCTCGCTG   300TCAGCGA AAGAGTCGGG CTGTCCCTGG AGACCGCCGA                     #     337          AAGGT CGTCGTCACC AAGGACA                                   - (2) INFORMATION FOR SEQ ID NO:78:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 112 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:78:                                #Val Ser Thr Val Lys Aspeu Val Ser Ser Lys                                    #                 15                                                          #Ala Gly Lys Pro Leu Leulu Lys Val Ile Gln                                    #             30                                                              #Leu Ser Thr Leu Val Valal Glu Gly Glu Ala                                    #         45                                                                  #Ala Val Lys Ala Pro Glyhr Phe Lys Ser Val                                    #     60                                                                      #Asp Met Ala Ile Leu Thrys Ala Met Leu Gln                                    # 80                                                                          #Leu Ser Leu Glu Thr Alaer Glu Arg Val Gly                                    #                 95                                                          #Val Val Val Thr Lys Asply Gln Ala Arg Lys                                    #            110                                                              - (2) INFORMATION FOR SEQ ID NO:79:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 360 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Genomic DNA                                         -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:79:                                #CGACGACGTC    60TCGGCGC TGAGCTGGTC AAAGAGGTCG CCAAGAAGAC                     #CGAAGGCCTG   120CCACCAC CGCCACCGTG CTCGCTCAGG CTCTGGTTCG                     #GAAGGCTGTC   180CCGGCGC CAACCCGCTC GGCCTCAAGC GTGGCATCGA                     #GGAGCAGATT   240AGTCGCT GCTGAAGTCG GCCAAGGAGG TCGAGACCAA                     #CGCCGAGGCC   300CGATCTC CGCCGGCGAC ACCCAGATCG GCGAGCTCAT                     #CTTCGGCCTG   360GCAACGA GGGTGTCATC ACCGTCGAGG AGTCGAACAC                     - (2) INFORMATION FOR SEQ ID NO:80:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 120 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:80:                                #Lys Glu Val Ala Lys Lysly Ala Glu Leu Val                                    #                 15                                                          #Thr Ala Thr Val Leu Alaly Asp Gly Thr Thr                                    #             30                                                              #Val Ala Ala Gly Ala Asnlu Gly Leu Arg Asn                                    #         45                                                                  #Ala Val Glu Ala Val Thrrg Gly Ile Glu Lys                                    #     60                                                                      #Glu Thr Lys Glu Gln Ileer Ala Lys Glu Val                                    # 80                                                                          #Thr Gln Ile Gly Glu Leule Ser Ala Gly Asp                                    #                 95                                                          #Glu Gly Val Ile Thr Valsp Lys Val Gly Asn                                    #            110                                                              -  Glu Glu Ser Asn Thr Phe Gly Leu                                            #        120                                                                  - (2) INFORMATION FOR SEQ ID NO:81:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 43 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Other                                               -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:81:                                # 43               CGAAA GCGTGGGGAG CGAACAGGAT TAG                            - (2) INFORMATION FOR SEQ ID NO:82:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 43 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Other                                               -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:82:                                # 43               CTACC TTAGGACCGT CATAGTTACG GGC                            - (2) INFORMATION FOR SEQ ID NO:83:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 20 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Other                                               -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:83:                                # 20               AAAAA                                                      - (2) INFORMATION FOR SEQ ID NO:84:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 31 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Other                                               -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:84:                                #          31      CTTTT TTTTTTTTTT T                                         - (2) INFORMATION FOR SEQ ID NO:85:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 31 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Other                                               -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:85:                                #          31      CATGC TSCTSCTSCT S                                         - (2) INFORMATION FOR SEQ ID NO:86:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 238 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Genomic DNA                                         -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:86:                                #GTTCGAGCTC    60TCGGAGC GCTCGACCTG AAGCTGCGCC ACGTCATGCA                     #CCAGGAAGAG   120GGGAGGT CGGGATCACG TTCATCTACG TGACCCACGA                     #ACAGATCGGC   180GTGACCG CATCGCGGTG ATGAACGCCG GCAACGTCGA                     #CATCGAAT     238TCTACGA CCGTCCCGCG ACGGTGTTCG TCGCCAGCTT                     - (2) INFORMATION FOR SEQ ID NO:87:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 79 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:87:                                #Lys Leu Arg His Val Metly Ala Leu Asp Leu                                    #                 15                                                          #Val Gly Ile Thr Phe Ilerg Ile Gln Arg Glu                                    #             30                                                              #Thr Met Ser Asp Arg Ileln Glu Glu Ala Leu                                    #         45                                                                  #Ile Gly Ser Pro Thr Gluly Asn Val Glu Gln                                    #     60                                                                      #Ala Ser Phe Ile Gluro Ala Thr Val Phe Val                                    # 75                                                                          - (2) INFORMATION FOR SEQ ID NO:88:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 1518 base                                                         (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Genomic DNA                                         -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:88:                                #CAGAACCGTG    60TGTTACA ATACCCCACC AGTTCCTCGA AGTAAACGAA                     #TGGGGTCCGG   120AAAATAT TCACAGCGAC GAAGCCCGGC CGATGCCTGA                     #GTGACGAAGG   180CGCTTTC CTGCGCGGAT TCTATTGTCG AGTCCGGGGT                     #TCAGATCCGC   240AATGTAA ATTCGTTGCG GAATCACTTG CATAGGTCCG                     #GACCGGCACA   300ACAGCCA CGACGGCTGT CCCCGAGGAG GACCTGCCCT                     #GCCCAAGGGC   360CAGAACC TGCAGAACAG ACGGCGGATT CCGCGGCACC                     #GGCCGTCGCG   420AGATCGA CCATGTCACG AAGCGCTTCG GCGACTACCT                     #GTCCGGGTGT   480CCATCGC GCCCGGGGAG TTCTTCTCCA TGCTCGGCCC                     #AGGGGCGATC   540CGTTGCG CATGATCGCG GGATTCGAGA CCCCGACTGA                     #CAACACGGTG   600CCGACGT GTCGAGGACC CCACCCAACA AGCGCAACGT                     #GTACGGCCCG   660CGCTGTT CCCGCACATG ACGGTCTGGG ACAACGTCGC                     #GCTGGAGATC   720TCGGCAA AGGCGAGGTC CGCAAGCGCG TCGACGAGCT                     #GCAGCAGCAG   780AATTTGC CGAGCGCAGG CCCGCCCAGC TGTCCGGCGG                     #CGATGAACCG   840CCCGGGC ACTGGTGAAC TACCCCAGCG CGCTGCTGCT                     #GCGCATCCAG   900ACCTGAA GCTGCGCCAC GTCATGCAGT TCGAGCTCAA                     #GCTCACGATG   960TCACGTT CATCTACGTG ACCCACGACC AGGAAGAGGC                     #CCCGACCGAG  1020CGGTGAT GAACGCCGGC AACGTCGAAC AGATCGGCAG                     #CAACCTCTGG  1080CCGCGAC GGTGTTCGTC GCCAGCTTCA TCGGACAGGC                     #TCTCGGCTCG  1140CCGGCCG CTCCAACCGC GATTACGTCG AGATCGACGT                     #CACCCTGATG  1200GCCCGGG CGAGACCACG ATCGAGCCCG GCGGGCACGC                     #CGGTGACGTC  1260GCATCCG GGTCACCCCG GGCTCCCAGG ACGCGCCGAC                     #GCGGCTCTCG  1320CCACCGT CACCGACCTG ACCTTCCAAG GTCCGGTGGT                     #GGATCTGCCG  1380ACGACTC GACCGTGATC GCCCACGTCG GCCCCGAGCA                     #CCTGGTGCTT  1440GCGACGA CGTGTACGTC AGCTGGGCAC CGGAAGCCTC                     #CTCCTGAGTC  1500TCCCCAC CACCGAGGAC CTCGAAGAGA TGCTCGACGA                     #1518              CGA                                                        - (2) INFORMATION FOR SEQ ID NO:89:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 376 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:89:                                #Phe Gly Asp Tyr Leu Alais Val Thr Lys Arg                                    #                 15                                                          #Gly Glu Phe Phe Ser Methe Ser Ile Ala Pro                                    #             30                                                              #Thr Leu Arg Met Ile Alays Gly Lys Thr Thr                                    #         45                                                                  #Arg Leu Glu Gly Ala Asphr Glu Gly Ala Ile                                    #     60                                                                      #Val Asn Thr Val Phe Glnro Asn Lys Arg Asn                                    # 80                                                                          #Trp Asp Asn Val Ala Tyrro His Met Thr Val                                    #                 95                                                          #Glu Val Arg Lys Arg Valys Leu Gly Lys Gly                                    #            110                                                              #Glu Phe Ala Glu Arg Argle Val Arg Leu Thr                                    #        125                                                                  #Arg Val Ala Leu Ala Argly Gly Gln Gln Gln                                    #    140                                                                      #Leu Asp Glu Pro Leu Glyro Ser Ala Leu Leu                                    #160                                                                          #Gln Phe Glu Leu Lys Argeu Arg His Val Met                                    #                175                                                          #Tyr Val Thr His Asp Glnly Ile Thr Phe Ile                                    #            190                                                              #Ala Val Met Asn Ala Glyet Ser Asp Arg Ile                                    #        205                                                                  #Ile Tyr Asp Arg Pro Alaly Ser Pro Thr Glu                                    #    220                                                                      #Ala Asn Leu Trp Ala Glyer Phe Ile Gly Gln                                    #240                                                                          #Val Glu Ile Asp Val Leuer Asn Arg Asp Tyr                                    #                255                                                          #Thr Thr Ile Glu Pro Glyla Arg Pro Gly Glu                                    #            270                                                              #Arg Ile Arg Val Thr Proet Val Arg Pro Glu                                    #        285                                                                  #Ala Cys Val Arg Ala Thrro Thr Gly Asp Val                                    #    300                                                                      #Val Arg Leu Ser Leu Alahe Gln Gly Pro Val                                    #320                                                                          #Val Gly Pro Glu Gln Asphr Val Ile Ala His                                    #                335                                                          #Tyr Val Ser Trp Ala Proro Gly Asp Asp Val                                    #            350                                                              #Ile Pro Thr Thr Glu Aspeu Pro Gly Asp Asp                                    #        365                                                                  -  Leu Glu Glu Met Leu Asp Asp Ser                                            #    375                                                                      - (2) INFORMATION FOR SEQ ID NO:90:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 33 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Other                                               -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:90:                                #         33       ATCGA GATCGACCAT GTC                                       - (2) INFORMATION FOR SEQ ID NO:91:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 31 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Other                                               -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:91:                                #          31      CGGGA AGCGTGACTC A                                         - (2) INFORMATION FOR SEQ ID NO:92:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 323 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Genomic DNA                                         -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:92:                                #CAAGGAGCCG    60AAGACTT CAACGACAAC GAGCAGTGGT TCGCCAAGGT                     #CATGGCCGCG   120AGGACAT AGGCGCCGAC CTGGTGATCC CCACCGAGTT                     #CAATCGCAAG   180TGGGATG GCTCAATGAG ATCAGCGAAG CCGGCGTGCC                     #CACCGCGCCG   240ACCTGTT GGACTCGAGC ATCGACGAGG GCCGCAAGTT                     #CGATATCCGC   300TGGTCGG TCTCGCCTAC AACAAGGCAG CCACCGGACG                     #               323TGGGA TCC                                                  - (2) INFORMATION FOR SEQ ID NO:93:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 1341 base                                                         (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Genomic DNA                                         -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:93:                                #ACATCGATCC    60CCTGGAG CCGACGAAAG GCACCCGCAC ATGTCCCGTG                     #TCGGCGGTGG   120CGAATGA CCGCACGCCG CACCTTGCGT CGCCGCTTCA                     #GCGGGTCCGA   180GCGGGCC TGACCCTCGG TTCGTCGTTC CTGGCGGCGT                     #CCCTGCGCGT   240AGCACCA CGTCACAGGA CAGCGGCCCC GCCAGCGGCG                     #CCGCCTCGGG   300CTCTATA TGGCCGACGG TTTCATCGCA GCGTTCCAGA                     #CCAAGGTCAA   360TACAAAG AAGACTTCAA CGACAACGAG CAGTGGTTCG                     #CCGAGTTCAT   420CGCAAGC AGGACATAGG CGCCGACCTG GTGATCCCCA                     #GCGTGCCCAA   480AAGGGCC TGGGATGGCT CAATGAGATC AGCGAAGCCG                     #GCAAGTTCAC   540CGTCAGG ACCTGTTGGA CTCGAGCATC GACGAGGGCC                     #CCGGACGCGA   600ACCGGCA TGGTCGGTCT CGCCTACAAC AAGGCAGCCA                     #GTCTGTTCTC   660GACGACC TCTGGGATCC CGCGTTCAAG GGCCGCGTCA                     #CGGAGAATCC   720GGCCTCG GCATGATCAT GCTCTCGCAG GGCAACTCGC                     #ACAGGGGGTC   780ATTCAGC AGGCGGTCGA TCTGGTCCGC GAACAGAACG                     #ACATCGCCAT   840CACCGGC AACGACTACG CCGACGACCT GGCCGCAGAA                     #ATCTGCAGTT   900TCCGGTG ACGTCGTGCA GCTGCAGGCG GACAACCCCG                     #CGTACACCAC   960TCCGGCG GCGACTGGTT CGTCGACACG ATGGTGATCC                     #CCAACTACGC  1020GCCGCCG AGGCGTGGAT CGACTACATC TACGACCGAG                     #ACGAACTCGC  1080TTCACCC AGTTCGTGCC CGCACTCTCG GACATGACCG                     #AGGTGCAGGC  1140GCATCGG CGGAGAACCC GCTGATCAAC CCGTCGGCCG                     #ACACTGCGTA  1200TGGGCGG CACTGACCGA CGAGCAGACG CAGGAGTTCA                     #TAAATGGCCC  1260GGCGGCT GACGCGGTGG TAGTGCCGAT GCGAGGGGCA                     #CGGACAAGGT  1320AGCATAA ATGGCCGGTG TCGCCACCAG CAGCCGTCAG                     #                1341TCC T                                                    - (2) INFORMATION FOR SEQ ID NO:94:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 393 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:94:                                #Ala Arg Met Thr Ala Argsp Pro His Leu Leu                                    #                 15                                                          #Gly Ala Ala Ala Ala Alarg Phe Ile Gly Gly                                    #             30                                                              #Ala Cys Gly Ser Asp Serer Ser Phe Leu Ala                                    #         45                                                                  #Gly Pro Ala Ser Gly Alahr Ser Gln Asp Ser                                    #     60                                                                      #Ala Asp Gly Phe Ile Alarp Pro Leu Tyr Met                                    # 80                                                                          #Asp Tyr Lys Glu Asp Pheer Gly Ile Thr Val                                    #                 95                                                          #Lys Glu Pro Leu Ser Argrp Phe Ala Lys Val                                    #            110                                                              #Pro Thr Glu Phe Met Alala Asp Leu Val Ile                                    #        125                                                                  #Glu Ile Ser Glu Ala Glyeu Gly Trp Leu Asn                                    #    140                                                                      #Leu Leu Asp Ser Ser Ilesn Leu Arg Gln Asp                                    #160                                                                          #Met Thr Gly Met Val Glyhe Thr Ala Pro Tyr                                    #                175                                                          #Asp Ile Arg Thr Ile Aspla Ala Thr Gly Arg                                    #            190                                                              #Val Ser Leu Phe Ser Aspla Phe Lys Gly Arg                                    #        205                                                                  #Ser Gln Gly Asn Ser Proly Met Ile Met Leu                                    #    220                                                                      #Ala Val Asp Leu Val Arglu Ser Ile Gln Gln                                    #240                                                                          #Leu His Arg Gln Arg Leuly Ser Asp Pro Ser                                    #                255                                                          #Ile Ala Gln Ala Tyr Serrg Arg Asn Ile Ala                                    #            270                                                              #Pro Asp Leu Gln Phe Ileeu Gln Ala Asp Asn                                    #        285                                                                  #Asp Thr Met Val Ile Proly Asp Trp Phe Val                                    #    300                                                                      #Ala Trp Ile Asp Tyr Ileln Lys Ala Ala Glu                                    #320                                                                          #Ala Phe Thr Gln Phe Valyr Ala Lys Leu Val                                    #                335                                                          #Ala Lys Val Asp Pro Alaet Thr Asp Glu Leu                                    #            350                                                              #Ala Glu Val Gln Ala Asneu Ile Asn Pro Ser                                    #        365                                                                  #Gln Thr Gln Glu Phe Asnla Leu Thr Asp Glu                                    #    380                                                                      -  Thr Ala Tyr Ala Ala Val Thr Gly Gly                                        #390                                                                          - (2) INFORMATION FOR SEQ ID NO:95:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 22 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Other                                               -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:95:                                #                 22ATCC CC                                                   - (2) INFORMATION FOR SEQ ID NO:96:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 21 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Other                                               -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:96:                                #21                GCGTC A                                                    - (2) INFORMATION FOR SEQ ID NO:97:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 861 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Genomic DNA                                         -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:97:                                #CTGGCACGCA    60TATCTCG CGATCTTCTT CCGTGGTGCC GTTCTTCTCG                     #GCCTGGGACT   120GACCGGC GGCTCGGTGT TCATGCCGAC GCTGACGTTC                     #TCGTTCGGCT   180CGACGCG TTCACGATGT ACCACGAGCA GATCTTCCGC                     #TACGTCATCG   240CACGGTG CTGTGCCTGT TGCTGGCGTT CCCGCTGGCC                     #CCGTTCTTCG   300CCGGTTC AAGAACCTGA TCCTGGGGCT GGTGATCCTG                     #GGCTGGGTGG   360CCGCACC ATTGCGTGGA AGACGATCCT GGCCGACGAA                     #TCCACCAGCT   420CGCCATC GGGCTGCTGC CTGACGAGGG CCGGCTGCTG                     #CCGCTGTACG   480CGGTCTG ACCTACAACT GGATCATCTT CATGATCCTG                     #TACTCGTCGG   540GATCGAC CCGCGTCTGC TGGAGGCCTC CCAGGACCTC                     #CTGGCCGGGA   600CGGCAAG GTGATCCTGC CGATGGCGAT GCCCGGGGTG                     #CTCGGCAGTA   660CATCCCG GCCGTCGGCG ACTTCATCAA CGCCGACTAT                     #AAGGACTATC   720GATCGGC AACGTGATCC AGAAGCAGTT CCTGGTCGTC                     #GTGCTCCTCT   780GCTGAGT CTGGGGCTGA TGTTGCTGAT CCTGATCGGC                     #CCGCACTGGC   840GGGTTCG GAGGATCTGG TATGACCACC CAGGCAGGCG                     #                 861ATC C                                                    - (2) INFORMATION FOR SEQ ID NO:98:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 259 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:98:                                #Ser Leu Ser Glu Thr Glyer Leu Ala Arg Thr                                    #                 15                                                          #Ala Trp Asp Phe Gly Asnro Thr Leu Thr Phe                                    #             30                                                              #Gln Ile Phe Arg Ser Phehr Met Tyr His Glu                                    #         45                                                                  #Leu Leu Leu Ala Phe Prola Thr Val Leu Cys                                    #     60                                                                      #Arg Phe Lys Asn Leu Ilela Phe Lys Ala Gly                                    # 80                                                                          #Thr Phe Leu Ile Arg Threu Pro Phe Phe Val                                    #                 95                                                          #Trp Val Val Thr Ala Leueu Ala Asp Glu Gly                                    #            110                                                              #Arg Leu Leu Ser Thr Sereu Pro Asp Glu Gly                                    #        125                                                                  #Trp Ile Ile Phe Met Ilely Leu Thr Tyr Asn                                    #    140                                                                      #Asp Pro Arg Leu Leu Gluer Leu Glu Lys Ile                                    #160                                                                          #Arg Ser Phe Gly Lys Valyr Ser Ser Ala Pro                                    #                175                                                          #Ala Gly Ser Met Leu Valet Pro Gly Val Leu                                    #            190                                                              #Ala Asp Tyr Leu Gly Serly Asp Phe Ile Asn                                    #        205                                                                  #Gln Lys Gln Phe Leu Valle Gly Asn Val Ile                                    #    220                                                                      #Ser Leu Gly Leu Met Leula Ala Ala Ala Leu                                    #240                                                                          #Arg Ala Leu Gly Ser Glual Leu Leu Tyr Thr                                    #                255                                                          -  Asp Leu Val                                                                - (2) INFORMATION FOR SEQ ID NO:99:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 277 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Genomic DNA                                         -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:99:                                #CAAGGACTTC    60GAGCCCG TACGCCGGTA GGCAAACTCA TGGGTTCGCT                     #CTTCCCCGGC   120TCGGTGC CGTGGCGATC AAGGGCGCCC TGGAGAAAGC                     #CTCCGCCGGC   180CTCGTCT CGTCGAGTAC GTGATCATGG GCCAAGTGCT                     #GGACGTCGCC   240CCGCCCG CCAGGCCGCC GTCGCCGCCG GCATCCCGTG                     #     277          AAGAT GTGCCTGTCG GGCATCG                                   - (2) INFORMATION FOR SEQ ID NO:100:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 92 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:100:                               #Gly Lys Leu Met Gly Serla Arg Thr Pro Val                                    #                 15                                                          #Ala Val Ala Ile Lys Glyly Ser Asp Leu Gly                                    #             30                                                              #Asp Pro Ala Arg Leu Valhe Pro Gly Val Asp                                    #         45                                                                  #Ala Gly Ala Gly Gln Metly Gln Val Leu Ser                                    #     60                                                                      #Ile Pro Trp Asp Val Alala Val Ala Ala Gly                                    # 80                                                                          #Gly Ileeu Thr Ile Asn Lys Met Cys Leu Ser                                    #                 90                                                          - (2) INFORMATION FOR SEQ ID NO:101:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 12 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (ix) FEATURE:                                                                     (A) NAME/KEY: Other                                                           (B) LOCATION: 1...1                                                 #Residue can be either Glu or Pro                                                       (A) NAME/KEY: Other                                                           (B) LOCATION: 2...2                                                 #Residue can be either Pro or Glu                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:101:                               #Arg Xaaaa Ala Asp Arg Gly Xaa Ser Lys Tyr                                    #                 10                                                          - (2) INFORMATION FOR SEQ ID NO:102:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 24 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:102:                               #Glu Lys Met Glu Lys Alaeu Phe Asp Ala Glu                                    #                 15                                                          -  Val Ser Val Ala Arg Asp Ser Ala                                                         20                                                               - (2) INFORMATION FOR SEQ ID NO:103:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 23 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:103:                               #Leu Ser Glu Phe Xaa Alala Thr Ser Gly Thr                                    #                 15                                                          -  Xaa Lys Gly Val Thr Met Glu                                                             20                                                               - (2) INFORMATION FOR SEQ ID NO:104:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 15 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:104:                               #Ala Asp Arg Val Glysp Ala Phe Ala Val Leu                                    #                 15                                                          - (2) INFORMATION FOR SEQ ID NO:105:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 9 amino                                                           (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:105:                               -  Xaa Ile Arg Val Gly Val Asn Gly Phe                                          1               5                                                           - (2) INFORMATION FOR SEQ ID NO:106:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 485 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: cDNA                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:106:                               #TCTCGCGGTG    60TCAACAC CGCCGCCTTC GAGTGGTACG TCGACTCGGG                     #GGCCTGCGGT   120GCGGGCA GTCCAGCTTC TACAGCGACT GGTACAGCCC                     #GCCGGCCTAC   180AGACCTA CAAGTGGGAG ACGTTCCTGA CCCAGGAGCT                     #GTCCATGGCC   240AGGGGGT CGACCCGAAC CGCAACGCGG CCGTCGGTCT                     #CGCCGGGTCG   300TGACGCT GGCGATCTAC CACCCGCAGC AGTTCCAGTA                     #CATCTCGATG   360TGAACCC GTCCGAGGGG TGGTGGCCGA TGCTGATCAA                     #CCCGAGCAGC   420GCTACAA GGCCAACGAC ATGTGGGGTC GCACCGAGGA                     #CAACACCCCC   480ACGACCC GATGGTCAAC ATCGGCAAGC TGGTCGCCAA                     #           485                                                               - (2) INFORMATION FOR SEQ ID NO:107:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 501 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Genomic DNA                                         -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:107:                               #GGCCGCGTGC    60GTGCGCG CAGTGCGCTT GCGTCCGTGA CCTTCGTCGC                     #CTACACGGTG   120GCACCGC ACTGGCGGCG ACGCCGGACT GGAGCGGGCG                     #AGAACCCGAC   180CCGACAA ACTCGGCACG AGTGTGGCCG CCCGCCAGCC                     #CACCGCGTCC   240ACACCTT CAGCACGTCC TGTGTGGGCA CCTGCGTGGC                     #CTGGGACGGC   300CGTCGAA CCCGACGATT CCGCAGCCCG CGCGCTACAC                     #CGACGTCCCG   360TCAACTA CAACTGGCAG TGGGAGTGCT TCCGCGGCGC                     #CGGGTCGATG   420CCGCGCG TTCGCTGGTG TTCTACGCCC CGACCGCCGA                     #GATCATGCCG   480GCACCGA NATCCTGGAN GGCCTCTGCA AGGGCACCGT                     #                 501GTA G                                                    - (2) INFORMATION FOR SEQ ID NO:108:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 180 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Genomic DNA                                         -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:108:                               #CGCCAACCCG    60GGCCCGA GGCCGAGGCG AACCTGCGGG GCTACTTCAC                     #GCGCAACTGC   120ACCTGCG GGGCATCCTC GCCCCGATCG GTGACGCGCA                     #GGCCGGCTGA   180TGCCGGT AGAGCTGCAG ACGGCCTACG ACACGTTCAT                     - (2) INFORMATION FOR SEQ ID NO:109:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 166 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:109:                               #Ala Ser Val Thr Phe Valla Arg Ser Ala Leu                                    #                 15                                                          #Ala Leu Ala Ala Thr Proly Ala Glu Gly Thr                                    #             30                                                              #Phe Ala Ser Asp Lys Leuyr Thr Val Val Thr                                    #         45                                                                  #Pro Asp Phe Ser Gly Glnla Arg Gln Pro Glu                                    #     60                                                                      #Cys Val Ala Thr Ala Serer Cys Val Gly Thr                                    # 80                                                                          #Pro Gln Pro Ala Arg Tyrer Asn Pro Thr Ile                                    #                 95                                                          #Tyr Asn Trp Gln Trp Gluln Trp Val Phe Asn                                    #            110                                                              #Tyr Ala Ala Ala Arg Sersp Val Pro Arg Glu                                    #        125                                                                  #Ser Met Phe Gly Thr Trpro Thr Ala Asp Gly                                    #    140                                                                      #Gly Thr Val Ile Met Prosp Gly Leu Cys Lys                                    #160                                                                          -  Val Ala Ala Tyr Pro Ala                                                                     165                                                          - (2) INFORMATION FOR SEQ ID NO:110:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 74 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:110:                               #Ala Val Thr Ala Ala Metro Gly Ala Asn Gln                                    #                 15                                                          #Leu Arg Gly Tyr Phe Thrlu Ala Glu Ala Asn                                    #             30                                                              #Gly Ile Leu Ala Pro Ileyr Tyr Asp Leu Arg                                    #         45                                                                  #Val Leu Pro Val Glu Leusn Cys Asn Ile Thr                                    #     60                                                                      -  Gln Thr Ala Tyr Asp Thr Phe Met Ala Gly                                    # 70                                                                          - (2) INFORMATION FOR SEQ ID NO:111:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 503 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Genomic DNA                                         -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:111:                               #GGCCGCGTTA    60GTGTTCT GGGCAGTGTC GGTGCAGCAG TCGCGGTTTC                     #CATCGAGGTG   120TTTCGAT ACCGACCGCC TCAGCGGATC CGTGTCCGGA                     #TGCGTTCGTC   180GGACCGG TGCGGAACCC GGCCTCGGGT GGGTCGGTGA                     #GAACTACCCG   240CCAAGGT CGGTGAGCAG TCGGTGGGCA CCTACGCGGT                     #CGGGGCGGGT   300TTCGACA AATCGGCGCC CATGGGCGCG GCCGACGCAT                     #TGTCGCANGG   360GACAACT GCCCGGACAC CAAGCTTGTC CTGGGCGGCA                     #TCACCCCCAC   420GACCTGA TCACCGTCGA TCCGCGACCG CTGGGCCGGT                     #GAAATCCGTT   480CGCGTCG CCGACCACGT GGCCGCCGTT GTGGTCTTCG                     #               503TGGCG GTC                                                  - (2) INFORMATION FOR SEQ ID NO:112:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 167 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:112:                               #Gly Ala Ala Val Ala Valal Leu Gly Ser Val                                    #                 15                                                          #Ile Pro Thr Ala Ser Alaln Thr Gly Val Ser                                    #             30                                                              #Ala Arg Gly Thr Gly Alale Glu Val Ile Phe                                    #         45                                                                  #Phe Val Asn Ala Leu Argrp Val Gly Asp Ala                                    #     60                                                                      #Tyr Ala Val Asn Tyr Proln Ser Val Gly Thr                                    # 80                                                                          #Met Gly Ala Ala Asp Alasp Lys Ser Ala Pro                                    #                 95                                                          #Cys Pro Asp Thr Lys Leurp Met Ala Asp Asn                                    #            110                                                              #Val Ile Asp Leu Ile Threr Xaa Gly Ala Gly                                    #        125                                                                  #Pro Thr Pro Met Pro Proeu Gly Arg Phe Thr                                    #    140                                                                      #Val Phe Gly Asn Pro Leual Ala Ala Val Val                                    #160                                                                          -  Arg Asp Ile Arg Gly Gly Gly                                                                 165                                                          - (2) INFORMATION FOR SEQ ID NO:113:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 1569 base                                                         (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Genomic DNA                                         -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:113:                               #GGGCCTCAAC    60TTGCGTA TGACGAAGAG GCCCGCCGTG GCCTCGAGCG                     #CGTGCTGGAG   120CCGTAAA GGTGACGTTG GGCCCGAAGG GTCGCAACGT                     #GGAGATCGAG   180CCCCCAC GATCACCAAC GATGGTGTGT CCATCGCCAA                     #CAAGAAGACC   240ACGAGAA GATCGGCGCT GAGCTGGTCA AAGAGGTCGC                     #TCTGGTTCGC   300GCGACGG CACCACCACC GCCACCGTGC TCGCTCAGGC                     #TGGCATCGAG   360ACGTCGC AGCCGGCGCC AACCCGCTCG GCCTCAAGCG                     #CGAGACCAAG   420CTGTCAC CCAGTCGCTG CTGAAGTCGG CCAAGGAGGT                     #CGAGCTCATC   480CCACCGC GGCGATTTCC GCCGGCGACA CCCAGATCGG                     #GTCGAACACC   540ACAAGGT CGGCAACGAG GGTGTCATCA CCGTCGAGGA                     #CATCTCGGGT   600TCGAGCT CACCGAGGGT ATGCGCTTCG ACAAGGGCTA                     #CATCCTGCTG   660ACGCCGA GCGCCAGGAA GCCGTCCTGG AGGATCCCTA                     #GGTCATCCAG   720TGTCGAC CGTCAAGGAT CTGCTCCCGC TGCTGGAGAA                     #GTCCACGCTG   780TGCTGAT CATCGCCGAG GACGTCGAGG GCGAGGCCCT                     #GGGCTTCGGT   840TCCGCGG CACCTTCAAG TCCGTCGCCG TCAAGGCTCC                     #GGTCGTCAGC   900CGATGCT GCAGGACATG GCCATCCTCA CCGGTGGTCA                     #GGCCCGCAAG   960TGTCCCT GGAGACCGCC GACGTCTCGC TGCTGGGCCA                     #CGATGCCATC  1020AGGACGA GACCACCATC GTCGAGGGCT CGGGCGATTC                     #CTACGACCGC  1080CTCAGAT CCGCGCCGAG ATCGAGAACA GCGACTCCGA                     #CAAGGCCGGA  1140AGCGCCT GGCCAAGCTG GCCGGCGGTG TTGCGGTGAT                     #CGTCCGCAAC  1200TGGAGCT CAAGGAGCGC AAGCACCGCA TCGAGGACGC                     #GCTGCAGTCG  1260TCGAAGA GGGCATCGTC GCCGGTGGCG GCGTGGCTCT                     #CAACATCGTC  1320ACGACCT CGGCCTGACG GGCGACGAGG CCACCGGTGC                     #GGAGCCCGGC  1380CGGCTCC GCTCAAGCAG ATCGCCTTCA ACGGCGGCCT                     #CGCGACCGGT  1440AGGTGTC CAACCTGCCC GCGGGTCACG GCCTCAACGC                     #CCGCTCGGCG  1500TGCTCAA GGCCGGCGTC GCCGACCCGG TGAAGGTCAC                     #CGTCGCCGAC  1560CGTCCAT CGCGGCTCTG TTCCTCACCA CCGAGGCCGT                     #       1569                                                                  - (2) INFORMATION FOR SEQ ID NO:114:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 523 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:114:                               #Ala Arg Arg Gly Leu Glula Tyr Asp Glu Glu                                    #                 15                                                          #Lys Val Thr Leu Gly Proeu Ala Asp Ala Val                                    #             30                                                              #Trp Gly Ala Pro Thr Ileal Leu Glu Lys Lys                                    #         45                                                                  #Ile Glu Leu Glu Asp Proer Ile Ala Lys Glu                                    #     60                                                                      #Glu Val Ala Lys Lys Thrla Glu Leu Val Lys                                    # 80                                                                          #Ala Thr Val Leu Ala Glnsp Gly Thr Thr Thr                                    #                 95                                                          #Ala Ala Gly Ala Asn Proly Leu Arg Asn Val                                    #            110                                                              #Val Glu Ala Val Thr Glnly Ile Glu Lys Ala                                    #        125                                                                  #Thr Lys Glu Gln Ile Serla Lys Glu Val Glu                                    #    140                                                                      #Gln Ile Gly Glu Leu Ileer Ala Gly Asp Thr                                    #160                                                                          #Gly Val Ile Thr Val Gluys Val Gly Asn Glu                                    #                175                                                          #Leu Thr Glu Gly Met Argly Leu Gln Leu Glu                                    #            190                                                              #Val Thr Asp Ala Glu Argle Ser Gly Tyr Phe                                    #        205                                                                  #Leu Leu Val Ser Ser Lyslu Asp Pro Tyr Ile                                    #    220                                                                      #Leu Glu Lys Val Ile Glnsp Leu Leu Pro Leu                                    #240                                                                          #Asp Val Glu Gly Glu Alaeu Ile Ile Ala Glu                                    #                255                                                          #Gly Thr Phe Lys Ser Valal Asn Lys Ile Arg                                    #            270                                                              #Arg Lys Ala Met Leu Glnly Phe Gly Asp Arg                                    #        285                                                                  #Val Ser Glu Arg Val Glyhr Gly Gly Gln Val                                    #    300                                                                      #Leu Gly Gln Ala Arg Lysla Asp Val Ser Leu                                    #320                                                                          #Val Glu Gly Ser Gly Aspsp Glu Thr Thr Ile                                    #                335                                                          #Ile Arg Ala Glu Ile Gluly Arg Val Ala Gln                                    #            350                                                              #Leu Gln Glu Arg Leu Alayr Asp Arg Glu Lys                                    #        365                                                                  #Ala Gly Ala Ala Thr Glual Ala Val Ile Lys                                    #    380                                                                      #Glu Asp Ala Val Arg Asnrg Lys His Arg Ile                                    #400                                                                          #Ala Gly Gly Gly Val Alalu Glu Gly Ile Val                                    #                415                                                          #Leu Gly Leu Thr Gly Aspro Ala Leu Asp Asp                                    #            430                                                              #Ala Leu Ser Ala Pro Leusn Ile Val Arg Val                                    #        445                                                                  #Pro Gly Val Val Ala Glusn Gly Gly Leu Glu                                    #    460                                                                      #Leu Asn Ala Ala Thr Glyro Ala Gly His Gly                                    #480                                                                          #Ala Asp Pro Val Lys Valeu Lys Ala Gly Val                                    #                495                                                          #Ile Ala Ala Leu Phe Leuln Asn Ala Ala Ser                                    #            510                                                              #Gluhr Thr Glu Ala Val Val Ala Asp Lys Pro                                    #        520                                                                  - (2) INFORMATION FOR SEQ ID NO:115:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 647 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Genomic RNA                                         -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:115:                               #GGGCCTCAAC    60TTGCGTA TGACGAAGAG GCCCGCCGTG GCCTCGAGCG                     #CGTGCTGGAG   120CCGTAAA GGTGACGTTG GGCCCGAAGG GTCGCAACGT                     #GGAGATCGAG   180CCCCCAC GATCACCAAC GATGGTGTGT CCATCGCCAA                     #CAAGAAGACC   240ACGAGAA GATCGGCGCT GAGCTGGTCA AAGAGGTCGC                     #TCTGGTTCGC   300GCGACGG CACCACCACC GCCACCGTGC TCGCTCAGGC                     #TGGCATCGAG   360ACGTCGC AGCCGGCGCC AACCCGCTCG GCCTCAAGCG                     #CGAGACCAAG   420CTGTCAC CCAGTCGCTG CTGAAGTCGG CCAAGGAGGT                     #CGAGCTCATC   480CCACCGC GGCGATTTCC GCCGGCGACA CCCAGATCGG                     #GTCGAACACC   540ACAAGGT CGGCAACGAG GGTGTCATCA CCGTCGAGGA                     #CATCTCGGGT   600TCGAGCT CACCGAGGGT ATGCGCTTCG ACAAGGGCTA                     #               647GCCGA GCGCCAGGAA GCCGTCCTGG AGGATCC                        - (2) INFORMATION FOR SEQ ID NO:116:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 927 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Genomic DNA                                         -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:116:                               #GCTCCCGCTG    60TGCTGGT CAGCTCCAAG GTGTCGACCG TCAAGGATCT                     #CGTCGAGGGC   120TCCAGGC CGGCAAGCCG CTGCTGATCA TCGCCGAGGA                     #CGTCGCCGTC   180CGCTGGT GGTCAACAAG ATCCGCGGCA CCTTCAAGTC                     #CATCCTCACC   240TCGGTGA CCGCCGCAAG GCGATGCTGC AGGACATGGC                     #CGTCTCGCTG   300TCAGCGA AAGAGTCGGG CTGTCCCTGG AGACCGCCGA                     #CGAGGGCTCG   360GCAAGGT CGTCGTCACC AAGGACGAGA CCACCATCGT                     #CGAGAACAGC   420CCATCGC CGGCCGGGTG GCTCAGATCC GCGCCGAGAT                     #CGGCGGTGTT   480ACCGCGA GAAGCTGCAG GAGCGCCTGG CCAAGCTGGC                     #GCACCGCATC   540CCGGAGC TGCCACCGAG GTGGAGCTCA AGGAGCGCAA                     #CGGTGGCGGC   600GCAACGC GAAGGCTGCC GTCGAAGAGG GCATCGTCGC                     #CGACGAGGCC   660AGTCGGC TCCTGCGCTG GACGACCTCG GCCTGACGGG                     #CGCCTTCAAC   720TCGTCCG CGTGGCGCTG TCGGCTCCGC TCAAGCAGAT                     #GGGTCACGGC   780CCGGCGT CGTTGCCGAG AAGGTGTCCA ACCTGCCCGC                     #CGACCCGGTG   840CCGGTGA GTACGAGGAC CTGCTCAAGG CCGGCGTCGC                     #CCTCACCACC   900CGGCGCT GCAGAACGCG GCGTCCATCG CGGCTCTGTT                     #            927   GACAA GCCGGAG                                              - (2) INFORMATION FOR SEQ ID NO:117:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 215 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:117:                               #Ala Arg Arg Gly Leu Glula Tyr Asp Glu Glu                                    #                 15                                                          #Lys Val Thr Leu Gly Proeu Ala Asp Ala Val                                    #             30                                                              #Trp Gly Ala Pro Thr Ileal Leu Glu Lys Lys                                    #         45                                                                  #Ile Glu Leu Glu Asp Proer Ile Ala Lys Glu                                    #     60                                                                      #Glu Val Ala Lys Lys Thrla Glu Leu Val Lys                                    # 80                                                                          #Ala Thr Val Leu Ala Glnsp Gly Thr Thr Thr                                    #                 95                                                          #Ala Ala Gly Ala Asn Proly Leu Arg Asn Val                                    #            110                                                              #Val Glu Ala Val Thr Glnly Ile Glu Lys Ala                                    #        125                                                                  #Thr Lys Glu Gln Ile Serla Lys Glu Val Glu                                    #    140                                                                      #Gln Ile Gly Glu Leu Ileer Ala Gly Asp Thr                                    #160                                                                          #Gly Val Ile Thr Val Gluys Val Gly Asn Glu                                    #                175                                                          #Leu Thr Glu Gly Met Argly Leu Gln Leu Glu                                    #            190                                                              #Val Thr Asp Ala Glu Argle Ser Gly Tyr Phe                                    #        205                                                                  -  Gln Glu Ala Val Leu Glu Asp                                                #    215                                                                      - (2) INFORMATION FOR SEQ ID NO:118:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 309 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:118:                               #Val Ser Thr Val Lys Aspeu Val Ser Ser Lys                                    #                 15                                                          #Ala Gly Lys Pro Leu Leulu Lys Val Ile Gln                                    #             30                                                              #Leu Ser Thr Leu Val Valal Glu Gly Glu Ala                                    #         45                                                                  #Ala Val Lys Ala Pro Glyhr Phe Lys Ser Val                                    #     60                                                                      #Asp Met Ala Ile Leu Thrys Ala Met Leu Gln                                    # 80                                                                          #Leu Ser Leu Glu Thr Alaer Glu Arg Val Gly                                    #                 95                                                          #Val Val Val Thr Lys Asply Gln Ala Arg Lys                                    #            110                                                              #Ser Asp Ala Ile Ala Glylu Gly Ser Gly Asp                                    #        125                                                                  #Asn Ser Asp Ser Asp Tyrrg Ala Glu Ile Glu                                    #    140                                                                      #Lys Leu Ala Gly Gly Valln Glu Arg Leu Ala                                    #160                                                                          #Val Glu Leu Lys Glu Argly Ala Ala Thr Glu                                    #                175                                                          #Ala Lys Ala Ala Val Glusp Ala Val Arg Asn                                    #            190                                                              #Leu Leu Gln Ser Ala Proly Gly Gly Val Ala                                    #        205                                                                  #Glu Ala Thr Gly Ala Asnly Leu Thr Gly Asp                                    #    220                                                                      #Lys Gln Ile Ala Phe Asneu Ser Ala Pro Leu                                    #240                                                                          #Lys Val Ser Asn Leu Proly Val Val Ala Glu                                    #                255                                                          #Glu Tyr Glu Asp Leu Leusn Ala Ala Thr Gly                                    #            270                                                              #Thr Arg Ser Ala Leu Glnsp Pro Val Lys Val                                    #        285                                                                  #Thr Thr Glu Ala Val Valla Ala Leu Phe Leu                                    #    300                                                                      -  Ala Asp Lys Pro Glu                                                         305                                                                          - (2) INFORMATION FOR SEQ ID NO:119:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 162 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Genomic DNA                                         -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:119:                               #CGCCACCCTG    60CGGAGAT CTCCGACGAC GCCACGTCGG TACGGTTGGT                     #CATCCAGGGC   120TGTTGAC GTTGGTGCTG TCCGGGCTCA ACGCCACCCT                     # 162              TGGCG CAGGCGGATT CCGTCGATCT TC                             - (2) INFORMATION FOR SEQ ID NO:120:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 1366 base                                                         (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Genomic DNA                                         -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:120:                               #CGGTCGGGTT    60CTGAACT CGACCTGGTT GGCCTGGGCC GTCGCGGTCG                     #GCGGCAGCGC   120GTCGTGC TGACCGAGGT GCACAACGCG TTGCGTCGGC                     #CGTTGCTGCT   180GTGCAAC TCCTGCGTAC CTACATCCTG CCGCTGGGCG                     #TGGTCGCCAC   240GCGATGG AGATCTCCGA CGACGCCACG TCGGTACGGT                     #CCCTCATCCA   300GTGTTGT TGACGTTGGT GCTGTCCGGG CTCAACGCCA                     #ACGTCGCGCG   360GACAGCT GGCGCAGGCG GATTCCGTCG ATCTTCCTCG                     #GCGCGAACGT   420GCGGTCG GTATCACCGT GATCATGGCC TATGTCTGGG                     #CTCTGCAGAA   480ACCGCAC TGGGCGTCAC TTCCATCGTT CTTGGCCTGG                     #TCCGGCTCGG   540ATCATCT CGGGTCTGCT GCTGCTGTTC GAGCAACCGT                     #GCGTGGTGGA   600GTCCCCA CCGCGGCGGG CCGGCCGTCC GCCCACGGCC                     #TGCCCAACGC   660GCAACAC ATATCGACAC CGGCGGCAAC CTGCTGGTAA                     #ACCGGCTGAC   720GCGTCGT TCACCAATTA CAGCCGGCCC GTGGGAGAGC                     #TGCTGTCGTC   780TTCAACG CCGCGGACAC CCCCGATGAT GTCTGCGAGA                     #TCTATCTCGG   840CTGCCCG AACTGCGCAC CGACGGACAG ATCGCCACGC                     #ACTCGGTCAG   900GAGAAGT CGATCCCGTT GCACACACCC GCGGTGGACG                     #GCCTNAACGG   960CGATGGG TCTGGTACGC CGCGCGCCGG CAGGAACTTC                     #CTGTGGCGTC  1020TTCGACA CGCCGGAACG GATCGCCTCG GCCATGCGGG                     #GTCTGGTCCG  1080GCAGACG ACGAACAGCA GGAGATCGCC GACGTGGTGC                     #TGAGGTTCAT  1140GAACGCC TCCAGCAGCC GGGTCAGGTA CCGACCGGGA                     #TCCCGGCGCG  1200GTGAGTC TGTCCGTGAT CGATCAGGAC GGCGACGTGA                     #CGGTACTGGC  1260GGCGACT TCCTGGGGCA GACCACGCTG ACGCGGGAAC                     #AGATCGAGCG  1320CTGGAGG AAGTCACCGT GCTGGAGATG GCCCGTGACG                     #               1366CCGA TCCTGCTGCA CGTGATCGGG GCCGTG                         - (2) INFORMATION FOR SEQ ID NO:121:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 455 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:121:                               #Ala Trp Ala Val Ala Valsn Ser Thr Trp Leu                                    #                 15                                                          #Leu Thr Glu Val His Asnal Leu Leu Val Val                                    #             30                                                              #Arg Pro Val Gln Leu Leuly Ser Ala Leu Ala                                    #         45                                                                  #Leu Leu Leu Leu Val Glnro Leu Gly Ala Leu                                    #     60                                                                      #Val Arg Leu Val Ala Thrsp Asp Ala Thr Ser                                    # 80                                                                          #Leu Ser Gly Leu Asn Alaeu Leu Thr Leu Val                                    #                 95                                                          #Trp Arg Arg Arg Ile Prola Pro Glu Asp Ser                                    #            110                                                              #Leu Ile Ala Val Gly Ileal Ala Arg Phe Ala                                    #        125                                                                  #Asn Val Gly Gly Leu Pheyr Val Trp Gly Ala                                    #    140                                                                      #Gly Leu Ala Leu Gln Asnhr Ser Ile Val Leu                                    #160                                                                          #Leu Leu Phe Glu Gln Prole Ser Gly Leu Leu                                    #                175                                                          #Thr Ala Ala Gly Arg Prorp Ile Thr Val Pro                                    #            190                                                              #Trp Arg Ala Thr His Ileal Val Glu Val Asn                                    #        205                                                                  #Asn Ala Glu Leu Ala Glyeu Leu Val Met Pro                                    #    220                                                                      #Gly Glu His Arg Leu Thryr Ser Arg Pro Val                                    #240                                                                          #Pro Asp Asp Val Cys Glusn Ala Ala Asp Thr                                    #                255                                                          #Glu Leu Arg Thr Asp Glyla Ala Ser Leu Pro                                    #            270                                                              #Glu Tyr Glu Lys Ser Ileyr Leu Gly Ala Ala                                    #        285                                                                  #Val Arg Ser Thr Tyr Leula Val Asp Asp Ser                                    #    300                                                                      #Glu Leu Arg Xaa Asn Glyla Ala Arg Arg Gln                                    #320                                                                          #Ile Ala Ser Ala Met Argsp Thr Pro Glu Arg                                    #                335                                                          #Asp Glu Gln Gln Glu Ileeu Arg Leu Ala Asp                                    #            350                                                              #Asn Gly Glu Arg Leu Glneu Val Arg Tyr Gly                                    #        365                                                                  #Phe Ile Val Asp Gly Argro Thr Gly Met Arg                                    #    380                                                                      #Asp Val Ile Pro Ala Argle Asp Gln Asp Gly                                    #400                                                                          #Thr Thr Leu Thr Arg Glusp Phe Leu Gly Gln                                    #                415                                                          #Glu Val Thr Val Leu Glula His Ala Leu Glu                                    #            430                                                              #His Arg Lys Pro Ile Leule Glu Arg Leu Val                                    #        445                                                                  -  Leu His Val Ile Gly Ala Val                                                #    455                                                                      - (2) INFORMATION FOR SEQ ID NO:122:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 898 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Genomic DNA                                         -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:122:                               #AAGACGCGGG    60CCTGGAA TGCGCGAACG TCTGAACACC CGACGCGAAA                     #GCTGCTTCTG   120TGTCGCG GATGAGCATC CAGTCCAAGT TGCTGCTGAT                     #ACGGTCCTCG   180CGGCTGC GGTGGTCGGT TTCATCGGCT ATCAGTCCGG                     #GCGCGGGTTG   240TGTTCGA CCGCCTCACC GACATCCGCG AGTCGCAGTC                     #CAGCACTGCC   300CGGACCT GAAGAACTCG ATGGTGATTT ACTCGCGCGG                     #GACGATCAAT   360GCGCGTT CAGCGACGGT TTCCGTCAGC TCGGCGATGC                     #CACCACCCTC   420CGTCATT GCGCCGTTAC TACGACCGGA CGTTCGCCAA                     #CCCCCAGCGC   480ACCGCGT CGACGTCCGC GCGCTCATCC CGAAATCCAA                     #CGCGTTCGAC   540TCTATAC CCCGCCGTTT CAGAACTGGG AGAAGGCGAT                     #GTTCTTCCGC   600GCAGCGC CTGGTCGGCC GCCAATGCCA GATTCAACGA                     #GGGCAACGTG   660GCTTCAA CTTCGAGGAT CTGATGCTGC TCGACCTCGA                     #CCCCTATCGC   720ACAAGGG GCCGGATCTC GGGACAAACA TCGTCAACGG                     #CGACTATGTC   780CGGAAGC CTACGAGAAG GCGGTCGCGT CGAACTCGAT                     #GTTCCTGTCC   840TCGGGTG GTACCTGCCT GCCGAGGAAC CGACCGCCTG                     #CGGAATTC     898AGGACCG AGTCGACGGT GTGATGGCGG TCCAGTTCCC                     - (2) INFORMATION FOR SEQ ID NO:123:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 1259 base                                                         (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Genomic DNA                                         -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:123:                               #ACCGGTGAGA    60GGCGCGG GGACAGTGGC GTGACACCGG GATGGGAGAC                     #CGCGAGAACC   120ACCGGAC AATCTGATGC GCTCGGACTC CCGGCTGTTC                     #GCCGACGAAT   180GGCCGAC GTCGTCGAGG GGGGAACCCC GCCGGAGGTC                     #GTCGAGGAGG   240CGGCACC ACGCTGGTGC AGCCGGTGAC CACCCGCTCC                     #GAGGCGTTAC   300CACCGGG ACGACGATCG AGGACGACTA TCTCGGCCAC                     #AAGATCGACA   360GGTGGAC CTGCCGGGAC TGCACTGGGT GATCGTGGCC                     #TCGACGGTGA   420CGCCCCG GTGGCGCAGT TCACCAGGAC CCTGGTGCTG                     #GTCCGTCCGA   480CGTGTCG CTGGCGGCCA TGCTGCTGGC GCGGTTGTTC                     #CTCGCTCTGC   540GGCCGGC GCCCAGCAGA TCAGCGGCGG TGACTACCGC                     #ATGAGTCGCA   600TGACGAA TTCGGCGATC TGACAACAGC TTTCAACGAC                     #CGGCTGATGC   660GGACGAG CTGCTCGGCG AGGAGCGCGC CGAGAACCAA                     #ACGATCGCCC   720CGAACCG GTGATGCAGC GCTACCTCGA CGGGGAGGAG                     #GAGTTGTCGC   780CGTCACG GTGATCTTCG CCGACATGAT GGGCCTCGAC                     #CAGTTCGACG   840CGAGGAA CTGATGGTGG TGGTCAACGA CCTGACCCGC                     #TACCTGGCCA   900TCTCGGG GTCGACCACG TGCGGACGCT GCACGACGGG                     #TTCGCGATCG   960CGTGCCG CGGCTGGACA ACGTCCGGCG CACGGTCAAT                     #CGGCTCCGCG  1020CATCGAC CGGCACGCCG CCGAGTCCGG GCACGACCTG                     #TTGGCGTACG  1080CGGGTCG GCGGCCAGCG GGCTGGTGGG GCGGTCCACG                     #CCCCAGCCCG  1140GGCGGTC GATGTCGCCT ACCAGGTGCA GCGCGGCTCC                     #TTCGTCGCCG  1200CTCGCGG GTGCACGAGG TCATGCAGGA AACTCTCGAC                     #GGCCACCCG   1259CGGCGAG CGCGGCGTCG AGACGGTCTG GCGGTTGCAG                     - (2) INFORMATION FOR SEQ ID NO:124:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 299 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:124:                               #Ser Glu His Pro Thr Argrp Asn Ala Arg Thr                                    #                 15                                                          #Arg Met Ser Ile Gln Seryr His Leu Leu Ser                                    #             30                                                              #Ile Leu Ser Ala Ala Valeu Leu Leu Thr Ser                                    #         45                                                                  #Ser Ser Leu Arg Ala Seryr Gln Ser Gly Arg                                    #     60                                                                      #Ser Gln Ser Arg Gly Leuhr Asp Ile Arg Glu                                    # 80                                                                          #Met Val Ile Tyr Ser Argsp Leu Lys Asn Ser                                    #                 95                                                          #Phe Ser Asp Gly Phe Arglu Ala Ile Gly Ala                                    #            110                                                              #Gln Ala Ala Ser Leu Arghr Ile Asn Thr Gly                                    #        125                                                                  #Thr Leu Asp Asp Ser Glyhr Phe Ala Asn Thr                                    #    140                                                                      #Lys Ser Asn Pro Gln Argrg Ala Leu Ile Pro                                    #160                                                                          #Gln Asn Trp Glu Lys Alayr Thr Pro Pro Phe                                    #                175                                                          #Ala Trp Ser Ala Ala Asnla Arg Asp Gly Ser                                    #            190                                                              #Val His Arg Phe Asn Phehe Phe Arg Glu Ile                                    #        205                                                                  #Asn Val Val Tyr Ser Alaeu Asp Leu Glu Gly                                    #    220                                                                      #Val Asn Gly Pro Tyr Argeu Gly Thr Asn Ile                                    #240                                                                          #Ala Val Ala Ser Asn Serlu Ala Tyr Glu Lys                                    #                255                                                          #Trp Tyr Leu Pro Ala Glual Thr Asp Phe Gly                                    #            270                                                              #Gly Leu Lys Asp Arg Valhe Leu Ser Pro Val                                    #        285                                                                  #Ilesp Gly Val Met Ala Val Gln Phe Pro Gly                                    #    295                                                                      - (2) INFORMATION FOR SEQ ID NO:125:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 419 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:125:                               #Asp Thr Gly Met Gly Asprg Gly Gln Trp Arg                                    #                 15                                                          #Asn Leu Met Arg Ser Aspeu Val Gly Pro Asp                                    #             30                                                              #Phe Leu Ala Asp Val Vallu Asn Arg Glu Lys                                    #         45                                                                  #Glu Ser Val Asp Arg Argro Glu Val Ala Asp                                    #     60                                                                      #Arg Ser Val Glu Glu Alaln Pro Val Thr Thr                                    # 80                                                                          #Asp Asp Tyr Leu Gly Hisly Thr Thr Ile Glu                                    #                 95                                                          #Leu Pro Gly Leu His Trpyr Ser Pro Val Asp                                    #            110                                                              #Ala Phe Ala Pro Val Alale Asp Thr Asp Glu                                    #        125                                                                  #Val Ile Ile Ile Phe Glyeu Val Leu Ser Thr                                    #    140                                                                      #Leu Phe Val Arg Pro Ileet Leu Leu Ala Arg                                    #160                                                                          #Ser Gly Gly Asp Tyr Argly Ala Gln Gln Ile                                    #                175                                                          #Phe Gly Asp Leu Thr Threu Ser Arg Asp Glu                                    #            190                                                              #Ile Lys Asp Glu Leu Leuer Arg Asn Leu Ser                                    #        205                                                                  #Met Leu Ser Leu Met Prolu Asn Gln Arg Leu                                    #    220                                                                      #Glu Glu Thr Ile Ala Glnrg Tyr Leu Asp Gly                                    #240                                                                          #Asp Met Met Gly Leu Asphr Val Ile Phe Ala                                    #                255                                                          #Leu Met Val Val Val Asneu Thr Ser Glu Glu                                    #            270                                                              #Glu Ser Leu Gly Val Asphe Asp Ala Ala Ala                                    #        285                                                                  #Ala Ser Cys Gly Leu Glyis Asp Gly Tyr Leu                                    #    300                                                                      #Val Asn Phe Ala Ile Glusn Val Arg Arg Thr                                    #320                                                                          #Glu Ser Gly His Asp Leusp Arg His Ala Ala                                    #                335                                                          #Ala Ala Ser Gly Leu Valle Asp Thr Gly Ser                                    #            350                                                              #Gly Ser Ala Val Asp Valla Tyr Asp Met Trp                                    #        365                                                                  #Pro Gly Ile Tyr Val Thrrg Gly Ser Pro Gln                                    #    380                                                                      #Leu Asp Phe Val Ala Alaal Met Gln Glu Thr                                    #400                                                                          #Thr Val Trp Arg Leu Glnlu Arg Gly Val Glu                                    #                415                                                          -  Gly His Pro                                                                - (2) INFORMATION FOR SEQ ID NO:126:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 27 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Other                                               -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:126:                               #             27   AGCGT GCTGAAC                                              - (2) INFORMATION FOR SEQ ID NO:127:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 26 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Other                                               -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:127:                               #              26  CCGAT CACGTG                                               - (2) INFORMATION FOR SEQ ID NO:128:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 33 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Other                                               -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:128:                               #         33       TTTCT GCCCTGGAAT GCG                                       - (2) INFORMATION FOR SEQ ID NO:129:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 32 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Other                                               -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:129:                               #          32      GGCCC TGCAACCGCC AG                                        - (2) INFORMATION FOR SEQ ID NO:130:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 27 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Other                                               -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:130:                               #             27   CCGTT CCGGCTC                                              - (2) INFORMATION FOR SEQ ID NO:131:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 27 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Other                                               -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:131:                               #             27   CAGTC CGGACGG                                              - (2) INFORMATION FOR SEQ ID NO:132:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 844 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Genomic DNA                                         -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:132:                               #CCGGCCGTCC    60GGCTCGG CGACTGGATC ACCGTCCCCA CCGCGGCGGG                     #CGGCGGCAAC   120TGGTGGA AGTCAACTGG CGTGCAACAC ATATCGACAC                     #CAGCCGGCCC   180CCAACGC CGAACTCGCC GGCGCGTCGT TCACCAATTA                     #CCCCGATGAT   240GGCTGAC CGTCGTCACC ACCTTCAACG CCGCGGACAC                     #CGACGGACAG   300TGTCGTC GGTCGCGGCG TCGCTGCCCG AACTGCGCAC                     #GCACACACCC   360ATCTCGG TGCGGCCGAA TACGAGAAGT CGATCCCGTT                     #CGCGCGCCGG   420CGGTCAG GAGCACGTAC CTGCGATGGG TCTGGTACGC                     #TCGCCTCGGC   480TAACGGC GTCGCCGACG ATTCGACACG CCGGAACGGA                     #AGATCGCCGA   540GCGTCCA CACTGCGCTT GGCAGACGAC GAACAGCAGG                     #GTCAGGTACC   600GTCCGTT ACGGCAACGG GGAACGCCTC CAGCAGCCGG                     #ATCAGGACGG   660TTCATCG TAGACGGCAG GGTGAGTCTG TCCGTGATCG                     #CCACGCTGAC   720GCGCGGG TGCTCGAGCG TGGCGACTTC CTGGGGCAGA                     #TGGAGATGGC   780CTGGCGA CCGCGCACGC GCTGGAGGAA GTCACCGTGC                     #TGATCGGGGC   840GAGCGCC TGGTGCACCG AAAGCCGATC CTGCTGCACG                     #            844                                                              - (2) INFORMATION FOR SEQ ID NO:133:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 742 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Genomic DNA                                         -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:133:                               #CACCGACATC    60GACGGTC CTCGCTGCGC GCATCGGTGT TCGACCGCCT                     #CTCGATGGTG   120CGCGCGG GTTGGAGAAT CAGTTCGCGG ACCTGAAGAA                     #CGGTTTCCGT   180GCAGCAC TGCCACGGAG GCGATCGGCG CGTTCAGCGA                     #TTACTACGAC   240CGACGAT CAATACCGGG CAGGCGGCGT CATTGCGCCG                     #CCGCGCGCTC   300ACACCAC CCTCGACGAC AGCGGAAACC GCGTCGACGT                     #GTTTCAGAAC   360ACCCCCA GCGCTATCTG CAGGCGCTCT ATACCCCGCC                     #GGCCGCCAAT   420TCGCGTT CGACGACGCG CGCGACGGCA GCGCCTGGTC                     #GGATCTGATG   480AGTTCTT CCGCGAGATC GTGCACCGCT TCAACTTCGA                     #TCTCGGGACA   540AGGGCAA CGTGGTGTAC TCCGCCTACA AGGGGCCGGA                     #GAAGGCGGTC   600GCCCCTA TCGCAACCGG GAACTGTCGG AAGCCTACGA                     #GCCTGCCGAG   660TCGACTA TGTCGGTGTC ACCGACTTCG GGTGGTACCT                     #CGGTGTGATG   720GGTTCCT GTCCCCGGTC GGGTTGAAGG ACCGAGTCGA                     #                742GAAT TC                                                   - (2) INFORMATION FOR SEQ ID NO:134:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 282 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:134:                               #Thr Val Pro Thr Ala Alaeu Gly Asp Trp Ile                                    #                 15                                                          #Glu Val Asn Trp Arg Alais Gly Arg Val Val                                    #             30                                                              #Val Met Pro Asn Ala Gluly Gly Asn Leu Leu                                    #         45                                                                  #Arg Pro Val Gly Glu Hishe Thr Asn Tyr Ser                                    #     60                                                                      #Ala Asp Thr Pro Asp Asphr Thr Phe Asn Ala                                    # 80                                                                          #Ser Leu Pro Glu Leu Arger Ser Val Ala Ala                                    #                 95                                                          #Gly Ala Ala Glu Tyr Glula Thr Leu Tyr Leu                                    #            110                                                              #Asp Asp Ser Val Arg Seris Thr Pro Ala Val                                    #        125                                                                  #Arg Arg Gln Glu Leu Argal Trp Tyr Ala Ala                                    #    140                                                                      #Pro Glu Arg Ile Ala Sersp Xaa Phe Asp Thr                                    #160                                                                          #Leu Ala Asp Asp Glu Glnla Ser Thr Leu Arg                                    #                175                                                          #Arg Tyr Gly Asn Gly Glual Val Arg Leu Val                                    #            190                                                              #Gly Met Arg Phe Ile Vally Gln Val Pro Thr                                    #        205                                                                  #Gln Asp Gly Asp Val Ileeu Ser Val Ile Asp                                    #    220                                                                      #Leu Gly Gln Thr Thr Leulu Arg Gly Asp Phe                                    #240                                                                          #Ala Leu Glu Glu Val Threu Ala Thr Ala His                                    #                255                                                          #Arg Leu Val His Arg Lysrg Asp Glu Ile Glu                                    #            270                                                              -  Pro Ile Leu Leu His Val Ile Gly Ala Val                                    #        280                                                                  - (2) INFORMATION FOR SEQ ID NO:135:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 247 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:135:                               #Ala Ser Val Phe Asp Argrg Ser Ser Leu Arg                                    #                 15                                                          #Gly Leu Glu Asn Gln Phelu Ser Gln Ser Arg                                    #             30                                                              #Ser Arg Gly Ser Thr Alaer Met Val Ile Tyr                                    #         45                                                                  #Phe Arg Gln Leu Gly Aspla Phe Ser Asp Gly                                    #     60                                                                      #Leu Arg Arg Tyr Tyr Asply Gln Ala Ala Ser                                    # 80                                                                          #Ser Gly Asn Arg Val Asphr Thr Leu Asp Asp                                    #                 95                                                          #Gln Arg Tyr Leu Gln Alaro Lys Ser Asn Pro                                    #            110                                                              #Lys Ala Ile Ala Phe Asphe Gln Asn Trp Glu                                    #        125                                                                  #Ala Asn Ala Arg Phe Asner Ala Trp Ser Ala                                    #    140                                                                      #Asn Phe Glu Asp Leu Metle Val His Arg Phe                                    #160                                                                          #Ser Ala Tyr Lys Gly Proly Asn Val Val Tyr                                    #                175                                                          #Tyr Arg Asn Arg Glu Leule Val Asn Gly Pro                                    #            190                                                              #Asn Ser Ile Asp Tyr Valys Ala Val Ala Ser                                    #        205                                                                  #Ala Glu Glu Pro Thr Alaly Trp Tyr Leu Pro                                    #    220                                                                      #Arg Val Asp Gly Val Metal Gly Leu Lys Asp                                    #240                                                                          -  Ala Val Gln Phe Pro Gly Ile                                                                 245                                                          - (2) INFORMATION FOR SEQ ID NO:136:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 45 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Genomic DNA                                         -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:136:                               #45                CGNCC CTGGCGGGTT CTGGCATGTG GCATC                          - (2) INFORMATION FOR SEQ ID NO:137:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 340 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Genomic DNA                                         -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:137:                               #CGCGCCGGCC    60CCGCCGC GGTGCCCGCC GGGGTGAGCG CCCCGGCGGT                     #CACGCTCAGC   120CCCGCCC GGTGTCCACG ATCGCGCCGG CGACCTCGGG                     #CTTCCGCGCC   180CCAAGGG CGTCACGATG GAGCCGCAGT CCAGCCGCGA                     #GAACGTGCCG   240TGCCGAA GCCGCGGGGC TGGGAGCACA TCCCGGACCC                     #GACAAACGCC   300TGCTGGC CGACCGGGTC AGNGGTAAAG GTCAGNAGTC                     #   340            AAACA CGTAGGCGAG TTCGACGGCA                                - (2) INFORMATION FOR SEQ ID NO:138:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 235 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: Genomic DNA                                         -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:138:                               #ACGCGATTGT    60GTNGAAC AGGTCGTTGC CGAAGCCGCG GAGGCCACCG                     #CTGCACCCGG   120GTCAGCG TTCCGGGTCC GGGTCCGGCC GCACCGCCAC                     #TCGCACCACC   180CCGCCCG CCCCCGGCGC CCCGGCGCTG CCGCTGGCCG                     #TGCAG        235GTTCCCG CCGTGGCGCC CGCGCCACAG CTGCTGGGAC                     - (2) INFORMATION FOR SEQ ID NO:139:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 15 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:139:                               #Leu Ala Cys Gly Ilela Arg Pro Trp Arg Val                                    #                 15                                                          - (2) INFORMATION FOR SEQ ID NO:140:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 113 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:140:                               #Gly Val Ser Ala Pro Alala Ala Val Pro Ala                                    #                 15                                                          #Pro Val Ser Thr Ile Alala Met Pro Ala Arg                                    #             30                                                              #Phe Ala Ala Lys Gly Valhr Leu Ser Glu Phe                                    #         45                                                                  #Arg Ala Leu Asn Ile Valer Ser Arg Asp Phe                                    #     60                                                                      #Pro Asp Pro Asn Val Proly Trp Glu His Ile                                    # 80                                                                          #Gly Gly Lys Gly Gln Xaaeu Ala Asp Arg Val                                    #                 95                                                          #His Val Gly Glu Phe Aspal Val Val Asp Lys                                    #            110                                                              -  Gly                                                                        - (2) INFORMATION FOR SEQ ID NO:141:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 73 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:141:                               #Ala Ala Asp Ala Thr Glulu Gln Val Val Ala                                    #                 15                                                          #Pro Gly Pro Gly Pro Alahe Lys Val Ser Val                                    #             30                                                              #Val Pro Pro Ala Pro Glyro Gly Ala Pro Gly                                    #         45                                                                  #Pro Pro Ala Pro Ala Valeu Ala Val Ala Pro                                    #     60                                                                      -  Pro Ala Val Ala Pro Ala Pro Gln Leu                                        # 70                                                                          - (2) INFORMATION FOR SEQ ID NO:142:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 273 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:142:                               #CAGCGGATAC    60AGGGGGG TCTCGGCCGC ATCGAGGCCC GGGTGGCCGA                     #CATCGACCAG   120CCAAGGG CTACTTCCCG CTGAGCTTCA CCGTCGCCGG                     #CGTGGCCACC   180TGACCGC CAACGTCACC GCGGCGGCCC CGACGGGCGC                     #CAAGCAGTCC   240TCATCGC CGGGCCGAGC CCGACCGGAT GGCAGCTGTC                     #        273       TCCGC GGTCATCGCC GCA                                       - (2) INFORMATION FOR SEQ ID NO:143:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 91 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:143:                               #Ile Glu Ala Arg Val Alaly Gly Leu Gly Arg                                    #                 15                                                          #Gly Tyr Phe Pro Leu Sersn Ala Ala Ala Lys                                    #             30                                                              #Pro Ile Val Thr Ala Asnle Asp Gln Asn Gly                                    #         45                                                                  #Ala Thr Gln Pro Leu Thrro Thr Gly Ala Val                                    #     60                                                                      #Gln Leu Ser Lys Gln Serer Pro Thr Gly Trp                                    # 80                                                                          #Alala Leu Ala Leu Met Ser Ala Val Ile Ala                                    #                 90                                                          - (2) INFORMATION FOR SEQ ID NO:144:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 554 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:144:                               #AACGAGTTAC    60GAGAATG TAACGTTCGA CCGGAGAACG CCGTCGGCAC                     #GTAACCGATC   120AGATCTC GGTTACCTTG GATTTCAGGC GGGGGAAGCA                     #CGCAAGCCGC   180ACCCAAA CAACATGAAA TTCACTGGAA TGACCGTGCG                     #GCAACCGTGG   240CGTCGGG GCGGCATGTC TGTTCGGCGG CGTGGCCGCG                     #ACCGGCACCG   300GGGCGCC CAGCCGGCCG AGTGCAACGC CAGCTCACTC                     #GCCAACCAGG   360CGGTCAG GCGCGTCAGT ACCTAGACAC CCACCCGGGC                     #CGGGGCTACT   420GATGAAC CAGCCGCGGC CCGAGGCCGA GGCGAACCTG                     #ATCGGTGACG   480GGCGGAG TACTACGACC TGCGGGGCAT CCTCGCCCCG                     #TACGACACGT   540CAACATC ACCGTGCTGC CGGTAGAGCT GCAGACGGCC                     #    554                                                                      - (2) INFORMATION FOR SEQ ID NO:145:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 136 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:145:                               #Ser Arg Arg Ala Leu Alaet Thr Val Arg Ala                                    #                 15                                                          #Val Ala Ala Ala Thr Valys Leu Phe Gly Gly                                    #             30                                                              #Glu Cys Asn Ala Ser Serly Ala Gln Pro Ala                                    #         45                                                                  #Gln Ala Arg Gln Tyr Leuer Ser Val Thr Gly                                    #     60                                                                      #Thr Ala Ala Met Asn Glnla Asn Gln Ala Val                                    # 80                                                                          #Gly Tyr Phe Thr Ala Asnlu Ala Asn Leu Arg                                    #                 95                                                          #Leu Ala Pro Ile Gly Aspsp Leu Arg Gly Ile                                    #            110                                                              #Pro Val Glu Leu Gln Thrsn Ile Thr Val Leu                                    #        125                                                                  -  Ala Tyr Asp Thr Phe Met Ala Gly                                            #    135                                                                      - (2) INFORMATION FOR SEQ ID NO:146:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 808 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:146:                               #CCGCAGCTGG    60GNGTGTG ACGGTAGACG TTCCGACCAA TCCAACGACG                     #GGATTCAGGA   120GCCAATT CAGTGCGGGC AACGGTGTCC GTCCACGAAG                     #TGGCCATCCT   180CGCCGGA AGTCAGCCGC AGTGGCGGGA ATCGCTGCGG                     #CCAGCAGCAC   240TGTTCGA GTGAGGACGG TGGGAGCACG GCCTCGTCGG                     #CGGCCCCTTC   300ATGGAGT CCGCGACCGA CGAGATGACC ACGTCGTCGG                     #AGCAGGTCCC   360GCCAACC TGATCGGCTC CGGCTGCGCG GCCTACGCCG                     #CGGCGTCGAA   420TCGGTGG CCGGGATGGC AGCCGATCCG GTGACGGTGG                     #CGCAGGTCAA   480CAGACGC TGTCCCAGGC GCTGTCCGGC CAGCTCAATC                     #ACGACGCGTT   540CTCGACG GCGGTGAGTT CACCGTGTTC GCGCCGACCG                     #TGCTGACCAA   600CCGGCCA CGCTGGAGAC CCTCAAGACG GACTCCGACA                     #TCGGCGAGCA   660CACGTCG TGCCCGGCCA GGCCGCGCCC GATCAGGTGG                     #TCAAGGTCAA   720GGGGCGC CGGTCACGGT GTCCGGGATG GCCGACCAGC                     #ATCTGATCGA   780GTGTGCG GTGGGGTGCA GACCGCCAAC GCGACGGTGT                     #            808   GCCGG CAGCGTAG                                             - (2) INFORMATION FOR SEQ ID NO:147:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 228 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:147:                               #Val Ala Gly Ile Ala Alarg Lys Ser Ala Ala                                    #                 15                                                          #Ser Glu Asp Gly Gly Serla Ala Ala Cys Ser                                    #             30                                                              #Ser Ala Met Glu Ser Alaer Ser Thr Ala Ser                                    #         45                                                                  #Pro Ser Ala Asp Pro Alahr Ser Ser Ala Ala                                    #     60                                                                      #Tyr Ala Glu Gln Val Proer Gly Cys Ala Ala                                    # 80                                                                          #Ala Asp Pro Val Thr Valal Ala Gly Met Ala                                    #                 95                                                          #Leu Ser Gln Ala Leu Serro Met Leu Gln Thr                                    #            110                                                              #Asp Thr Leu Asp Gly Glyln Val Asn Leu Val                                    #        125                                                                  #Ala Phe Ala Lys Ile Aspla Pro Thr Asp Asp                                    #    140                                                                      #Ser Asp Met Leu Thr Asnhr Leu Lys Thr Asp                                    #160                                                                          #Ala Ala Pro Asp Gln Valal Val Pro Gly Gln                                    #                175                                                          #Pro Val Thr Val Ser Glyhr Val Glu Gly Ala                                    #            190                                                              #Ser Val Val Cys Gly Glyys Val Asn Asp Ala                                    #        205                                                                  #Ile Asp Thr Val Leu Metla Thr Val Tyr Leu                                    #    220                                                                      -  Pro Pro Ala Ala                                                             225                                                                          - (2) INFORMATION FOR SEQ ID NO:148:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 22 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:148:                               #                 22NTGY GC                                                   - (2) INFORMATION FOR SEQ ID NO:149:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 21 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:149:                               #21                NACNG G                                                    - (2) INFORMATION FOR SEQ ID NO:150:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 102 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:150:                               #GCCGGGATCG    60CCGGCTG TGCGGCCTAC GTGCAACAGG TGCCGGACGG                     # 102              AGCTC GCCCGTAGCG ACCGCCGCGT AT                             - (2) INFORMATION FOR SEQ ID NO:151:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 683 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:151:                               #TCATGAACAT    60AACCGCC GATCATCCAC TGCAGGAAGG AATCTCACGA                     #GTCTGTCGCT   120CTTGCCG GAGCGGGTTT CGCGATGACC GCCGCCGTCG                     #CCTACGTGCA   180AGCGCCG CAGCCGCGCC GGTCGGACCG GGGTGTGCGG                     #TGGCCACCGC   240GGGCCGG GATCGGTGCA GGGCATGGCG AGCTCGCCGG                     #AGCTCAACCC   300CCGCTGC TCACCACGCT CTCGCAGGCG ATCTCGGGTC                     #CGCCGACCAA   360GTCGACA CGTTCAACGG CGGCCAGTTC ACCGTGTTCG                     #ATTCCGACCT   420AAGATCG ATCCGGCCAC GCTGGAGACC CTCAAGACCG                     #ATCAGGTGGT   480CTCACCT ACCACGTCGT GCCCGGCCAG GCCGCGCCCG                     #CCGACCAGCT   540ACGGTGG AGGGGGCGCC GGTCACGGTG TCCGGGATGG                     #CGACGGTGTA   600GCGTCGG TGGTGTGCGG TGGGGTGCAG ACCGCCAACG                     #CAGAAGAGGG   660GTGCTGA TGCCGCCGGC AGCGTAGCCG GGCGGCACCA                     #               683CTCCC CCG                                                  - (2) INFORMATION FOR SEQ ID NO:152:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 231 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:152:                               #Arg Arg Ser Ser Thr Alaro Pro Ala Asn Asn                                    #                 15                                                          #Met Lys Thr Leu Ala Glyle Met Asn Ile Ser                                    #             30                                                              #Leu Ser Leu Gly Thr Alahr Ala Ala Val Gly                                    #         45                                                                  #Gly Cys Ala Ala Tyr Valla Pro Val Gly Pro                                    #     60                                                                      #Gln Gly Met Ala Ser Serly Pro Gly Ser Val                                    # 80                                                                          #Leu Leu Thr Thr Leu Serla Ala Asp Asn Pro                                    #                 95                                                          #Val Asn Leu Val Asp Thrln Leu Asn Pro Asn                                    #            110                                                              #Pro Thr Asn Asp Ala Phehe Thr Val Phe Ala                                    #        125                                                                  #Leu Lys Thr Asp Ser Aspla Thr Leu Glu Thr                                    #    140                                                                      #Val Pro Gly Gln Ala Alaeu Thr Tyr His Val                                    #160                                                                          #Val Glu Gly Ala Pro Vally Glu His Val Thr                                    #                175                                                          #Val Asn Asp Ala Ser Valla Asp Gln Leu Lys                                    #            190                                                              #Thr Val Tyr Leu Ile Aspln Thr Ala Asn Ala                                    #        205                                                                  #Gly Thr Thr Glu Glu Glyro Ala Ala Pro Gly                                    #    220                                                                      -  Pro Pro His Pro Ala Ser Pro                                                #230                                                                          - (2) INFORMATION FOR SEQ ID NO:153:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 1125 base                                                         (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:153:                               #GGCCGCGTTA    60GTGTTCT GGGCAGTGTC GGTGCAGCAG TCGCGGTTTC                     #CATCGAGGTG   120TTTCGAT ACCGACCGCC TCAGCGGATC CGTGTCCGGA                     #TGCGTTCGTC   180GGACCGG TGCGGAACCC GGCCTCGGGT GGGTCGGTGA                     #GAACTACCCG   240CCAAGGT CGGTGAGCAG TCGGTGGGCA CCTACGCGGT                     #CGGGGCGGGT   300TTCGACA AATCGGCGCC CATGGGCGCG GCCGACGCAT                     #TGTCGCANGG   360GACAACT GCCCGGACAC CAAGCTTGTC CTGGGCGGCA                     #TCACCCCCAC   420GACCTGA TCACCGTCGA TCCGCGACCG CTGGGCCGGT                     #GAAATCCGTT   480CGCGTCG CCGACCACGT GGCCGCCGTT GTGGTCTTCG                     #GGCCGAAGTC   540GGTGGCG GTCCGCTGCC GCAGATGAGC GGCACCTACG                     #TGCCGGCCCA   600GCGCTCG ACGATCCGTT CTGCTCGCCC GGCTTCAACC                     #GCCTGGAACC   660GACAACG GCATGGTGGA GGAAGCCGCG AACTTCGCCC                     #CGCGGGGCGA   720GAGCTGC CCGAGGCGCC CTACCTGCAC CTGTTCGTCC                     #TCACCGCATC   780GACGCCG GACCGCTGCG CGAAGGCGAC GCAGTGCGTT                     #AGATGCATGC   840GTGACCG CCACCGCGCC CGCGGAGATC CTCGTCTGGG                     #CTGCTCGCCG   900GCATAAG CGAATAGGAG TCCTGCTGGC CGGCGCAGCA                     #AGCACAACCG   960ACCTGGA CCCGGGCCGT CGGCGGCACC GGCCCCGACG                     #CCTCTGGCCG  1020TCCCGGA CTCGTCCCGG TGACCGTCGC GGTCGACGAA                     #CTGTCGGTGT  1080CCAGCCC CGGGAGGCCC TGGTGCCGCA GGGTTGGACG                     #                1125CCG CGGCTGGCCG CGTGGGCCCC GGACG                          - (2) INFORMATION FOR SEQ ID NO:154:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 748 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:154:                               #Gly Ala Ala Val Ala Valal Leu Gly Ser Val                                    #                 15                                                          #Ile Pro Thr Ala Ser Alaln Thr Gly Val Ser                                    #             30                                                              #Ala Arg Gly Thr Gly Alale Glu Val Ile Phe                                    #         45                                                                  #Phe Val Asn Ala Leu Argrp Val Gly Asp Ala                                    #     60                                                                      #Tyr Ala Val Asn Tyr Proln Ser Val Gly Thr                                    # 80                                                                          #Met Gly Ala Ala Asp Alasp Lys Ser Ala Pro                                    #                 95                                                          #Cys Pro Asp Thr Lys Leurp Met Ala Asp Asn                                    #            110                                                              #Val Ile Asp Leu Ile Threr Xaa Gly Ala Gly                                    #        125                                                                  #Pro Thr Pro Met Pro Proeu Gly Arg Phe Thr                                    #    140                                                                      #Val Phe Gly Asn Pro Leual Ala Ala Val Val                                    #160                                                                          #Glu Pro Arg Gly Leu Asnly Gly Pro Arg Leu                                    #                175                                                          #His Arg Thr Tyr Arg Glyrg Gly Leu Tyr Thr                                    #            190                                                              #Ile Leu Glu Ala Ser Proyr Ser Ser Glu Arg                                    #        205                                                                  #Ala Ser Pro Ala Ser Prola Leu Ala Leu Glu                                    #    220                                                                      #Arg Pro Arg Gly Leu Tyrys Tyr Ser Ser Glu                                    #240                                                                          #Ala Leu Ala His Ile Sersn Leu Glu Pro Arg                                    #                255                                                          #Leu Ala Ala Ser Pro Alala Thr Tyr Arg Ala                                    #            270                                                              #Leu Gly Leu Gly Leu Alaet Glu Thr Val Ala                                    #        285                                                                  #Glu Ala Leu Ala Ala Argla Ser Asn Pro His                                    #    300                                                                      #Gly Leu Asn Ser Glu Argro Arg Gly Leu Tyr                                    #320                                                                          #Leu Ala Leu Ala Pro Argeu Glu Pro Arg Gly                                    #                335                                                          #Pro His Glu Val Ala Leuis Ile Ser Leu Glu                                    #            350                                                              #Val Ala Leu Thr His Argly Leu Tyr Gly Leu                                    #        365                                                                  #Gly Leu Tyr Pro Arg Leuer Pro Ala Leu Ala                                    #    380                                                                      #Ser Pro Ala Leu Ala Valeu Gly Leu Tyr Ala                                    #400                                                                          #Arg Ala Leu Ala Ser Gluro His Glu Thr His                                    #                415                                                          #Ala Arg Gly Val Ala Leueu Tyr Gly Leu Asn                                    #            430                                                              #Leu Ala Pro Arg Ala Leula Thr His Arg Ala                                    #        445                                                                  #Leu Thr Arg Pro Gly Leulu Leu Glu Val Ala                                    #    460                                                                      #Leu Tyr Leu Glu Gly Leuer Ala Leu Ala Gly                                    #480                                                                          #Ala Ser Asn Ala Arg Glyeu Ala Ala Leu Ala                                    #                495                                                          #Tyr Ala Arg Gly Ala Argla Leu Ala Gly Leu                                    #            510                                                              #Ala Arg Gly Ala Arg Glyis Arg Ala Leu Ala                                    #        525                                                                  #Arg Gly Thr His Arg Threr Ile Leu Glu Ala                                    #    540                                                                      #Ala Val Ala Leu Gly Leula Arg Gly Ala Leu                                    #560                                                                          #Pro Arg Ala Ser Pro Glyis Arg Gly Leu Tyr                                    #                575                                                          #Gly Leu Ala Arg Gly Threr Asn Ala Arg Gly                                    #            590                                                              #Gly Thr His Arg Ala Arger Glu Arg Ala Arg                                    #        605                                                                  #Arg Gly Ala Arg Gly Glyyr Ala Ser Pro Ala                                    #    620                                                                      #Arg Ser Glu Arg Gly Leula Arg Gly Thr His                                    #640                                                                          #Val Ala Leu Ala Arg Glyrg Gly Ala Leu Ala                                    #                655                                                          #Gly Leu Tyr Pro Arg Glyro Arg Gly Leu Tyr                                    #            670                                                              #Tyr Leu Glu Ala Ser Prola Leu Ala Gly Leu                                    #        685                                                                  #Ala Leu Gly Leu Tyr Alaeu Gly Leu Tyr Val                                    #    700                                                                      #Ala Leu Ala Ala Leu Alala Arg Gly Pro Arg                                    #720                                                                          #Ala Leu Gly Leu Tyr Proyr Ala Arg Gly Val                                    #                735                                                          #Leu Tyrly Leu Tyr Ala Arg Gly Pro Arg Gly                                    #            745                                                              - (2) INFORMATION FOR SEQ ID NO:155:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 1012 base                                                         (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:155:                               #GCATCCATCG    60ATTCGGG ATGCTACAAA TCCGCCGGCC CGATATGGTC                     #GCTGAGCCTG   120CCGCACT GGCACCATCT CATGCAGGTC TGGACAATGA                     #CTTCCTCAAC   180AGGGCCC GGAACGACTG ACCATTCAGC AGTGGGACAC                     #GGGCAAGGCG   240TGGACCG CAACCGGTTG ACCCGGGAGT GGTTCCACTC                     #GCTGGGCTAC   300CCGGTGA AGGTGCCGAC GAGTTCGAGG GCACGCTGGA                     #CACCCCGAAC   360CGTGGTC GCTGGGCGTG GGCATCAACT TCAGCTACAC                     #CGGTGATTCC   420GTTACGG CCTCAACTTC GCCGACCCGC TGCTGGGCTT                     #CAACGGCCCC   480CGCTGTT CCCGGGTGTC TCGATCACGG CGGACCTGGG                     #TTCCGTGGTG   540TCGCGAC CTTCTCCGTG GACGTGGCCG GCCCCGGTGG                     #GCGTCCGTTC   600ACGGCAC GGTCACCGGT GCTGCCGGTG GTGTGCTGCT                     #CTGCTGAAAC   660CGTCGAC CGGCGACAGC GTCACCACCT ACGGCGCACC                     #CTTCACGCTG   720ATCACGA TGGAGGCCCC CCGGCGTCAA CCGGGGCCCG                     #TGCGCGCGCG   780CGAGGTT CGATCGAAGT GGCCGACTGC GGCAAACGCC                     #ACTCCACCTC   840GACGCAG GGTCTGGTGG TAGTCGAATG TCATCCTGTG                     #GGCACGTACG   900CGACGGC CGGGGTTCCG GTGTGTGGGC GCCGGCCTTG                     #CCGGACGGCC   960TCGTGAT GTGACGAGCG TCGCAGTGTT TGCCGGCAAC                     #AG          1012GCATCCG TCCAGCGAAC CCGGGGGATC CAAAGAATTC                     - (2) INFORMATION FOR SEQ ID NO:156:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 336 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:156:                               #Ser Ala Gly Pro Ile Trper Gly Cys Tyr Lys                                    #                 15                                                          #Leu Ala Pro Ser His Alaeu Cys Ser Pro Ala                                    #             30                                                              #His Gly Gln Gly Pro Glueu Ser Leu Gly Val                                    #         45                                                                  #Leu Asn Gly Val Phe Proln Trp Asp Thr Phe                                    #     60                                                                      #Phe His Ser Gly Lys Alaeu Thr Arg Glu Trp                                    # 80                                                                          #Glu Phe Glu Gly Thr Leuly Glu Gly Ala Asp                                    #                 95                                                          #Ser Leu Gly Val Gly Ileal Gly Phe Pro Trp                                    #            110                                                              #Tyr Asp Gly Tyr Gly Leuhr Pro Asn Ile Thr                                    #        125                                                                  #Asp Ser Ile Val Thr Proeu Leu Gly Phe Gly                                    #    140                                                                      #Asp Leu Gly Asn Gly Proal Ser Ile Thr Ala                                    #160                                                                          #Asp Val Ala Gly Pro Glyla Thr Phe Ser Val                                    #                175                                                          #Thr Val Thr Gly Ala Alaer Asn Ala His Gly                                    #            190                                                              #Leu Ile Ser Ser Thr Glyrg Pro Phe Ala Arg                                    #        205                                                                  #Lys His Glu Leu Thr Thryr Gly Ala Pro Leu                                    #    220                                                                      #Gly Pro Leu His Ala Glyro Gly Val Asn Arg                                    #240                                                                          #Pro Thr Ala Ala Asn Alaal Arg Ser Lys Trp                                    #                255                                                          #Gly Leu Val Val Val Gluer Ser Leu Thr Gln                                    #            270                                                              #Arg Arg Asp Gly Arg Glyro Pro His Arg Pro                                    #        285                                                                  #Tyr Gly Gly Asp Arg Argro Ala Leu Gly Thr                                    #    300                                                                      #Gly Asn Pro Asp Gly Proal Ala Val Phe Ala                                    #320                                                                          #Gly Gly Ser Lys Glu Phero Ser Ser Glu Pro                                    #                335                                                          - (2) INFORMATION FOR SEQ ID NO:157:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 480 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:157:                               #CTTGTCGACG    60TCAACAC CCCTGCGTTC GAGTGGTTCT ACGAGTCCGG                     #GTCTCGGGGC   120GCGGACA GTCCAGCTTC TACAGCGACT GGTACCAGCC                     #GCCGACGTGG   180ACACCTA CAAGTGGGAG ACGTTCCTGA CCCAGGAGCT                     #GTCGATGGCG   240GCGGAGT GTCGCGCACC GGCAACGCGT TCGTCGGCCT                     #CGCCTCGTCG   300TGACCTA CGCGATCCAT CACCCGCAGC AGTTCATCTA                     #GCTGGCGATG   360TGAACCC GTCCGAGGGC TGGTGGCCGA TGCTGATCGG                     #CCCGGCGTGG   420GCTTCAA CGCCGAGAGC ATGTGGGGCC CGTCCTCGGA                     #CCGGATCTGG   480CGATGGT CAACATCAAC CAGCTGGTGG CCAACAACAC                     - (2) INFORMATION FOR SEQ ID NO:158:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 161 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:158:                               #Glu Trp Phe Tyr Glu Sersn Thr Pro Ala Phe                                    #                 15                                                          #Gln Ser Ser Phe Tyr Seret Pro Val Gly Gly                                    #             30                                                              #Gln Asn Tyr Thr Tyr Lyser Arg Gly Asn Gly                                    #         45                                                                  #Thr Trp Leu Glu Ala Asnhr Gln Glu Leu Pro                                    #     60                                                                      #Val Gly Leu Ser Met Alahr Gly Asn Ala Phe                                    # 80                                                                          #His Pro Gln Gln Phe Ilehr Tyr Ala Ile His                                    #                 95                                                          #Pro Ser Glu Gly Trp Trper Gly Phe Leu Asn                                    #            110                                                              #Ala Gly Gly Phe Asn Alaeu Ala Met Asn Asp                                    #        125                                                                  #Ala Trp Lys Arg Asn Aspro Ser Ser Asp Pro                                    #    140                                                                      #Asn Asn Thr Arg Ile Trpsn Gln Leu Val Ala                                    #160                                                                          -  Ile                                                                        - (2) INFORMATION FOR SEQ ID NO:159:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 1626 base                                                         (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:159:                               #GGGCCTCAAC    60TTGCGTA TGACGAAGAG GCCCGCCGTG GCCTCGAGCG                     #CGTGCTGGAG   120CCGTAAA GGTGACGTTG GGCCCGAAGG GTCGCAACGT                     #GGAGATCGAG   180CCCCCAC GATCACCAAC GATGGTGTGT CCATCGCCAA                     #CAAGAAGACC   240ACGAGAA GATCGGCGCT GAGCTGGTCA AAGAGGTCGC                     #TCTGGTTCGC   300GCGACGG CACCACCACC GCCACCGTGC TCGCTCAGGC                     #TGGCATCGAG   360ACGTCGC AGCCGGCGCC AACCCGCTCG GCCTCAAGCG                     #CGAGACCAAG   420CTGTCAC CCAGTCGCTG CTGAAGTCGG CCAAGGAGGT                     #CGAGCTCATC   480CCACCGC GGCGATTTCC GCCGGCGACA CCCAGATCGG                     #GTCGAACACC   540ACAAGGT CGGCAACGAG GGTGTCATCA CCGTCGAGGA                     #CATCTCGGGT   600TCGAGCT CACCGAGGGT ATGCGCTTCG ACAAGGGCTA                     #CATCCTGCTG   660ACGCCGA GCGCCAGGAA GCCGTCCTGG AGGATCCCTA                     #GGTCATCCAG   720TGTCGAC CGTCAAGGAT CTGCTCCCGC TGCTGGAGAA                     #GTCCACGCTG   780TGCTGAT CATCGCCGAG GACGTCGAGG GCGAGGCCCT                     #GGGCTTCGGT   840TCCGCGG CACCTTCAAG TCCGTCGCCG TCAAGGCTCC                     #GGTCGTCAGC   900CGATGCT GCAGGACATG GCCATCCTCA CCGGTGGTCA                     #GGCCCGCAAG   960TGTCCCT GGAGACCGCC GACGTCTCGC TGCTGGGCCA                     #CGATGCCATC  1020AGGACGA GACCACCATC GTCGAGGGCT CGGGCGATTC                     #CTACGACCGC  1080CTCAGAT CCGCGCCGAG ATCGAGAACA GCGACTCCGA                     #CAAGGCCGGA  1140AGCGCCT GGCCAAGCTG GCCGGCGGTG TTGCGGTGAT                     #CGTCCGCAAC  1200TGGAGCT CAAGGAGCGC AAGCACCGCA TCGAGGACGC                     #GCTGCAGTCG  1260TCGAAGA GGGCATCGTC GCCGGTGGCG GCGTGGCTCT                     #CAACATCGTC  1320ACGACCT CGGCCTGACG GGCGACGAGG CCACCGGTGC                     #GGAGCCCGGC  1380CGGCTCC GCTCAAGCAG ATCGCCTTCA ACGGCGGCCT                     #CGCGACCGGT  1440AGGTGTC CAACCTGCCC GCGGGTCACG GCCTCAACGC                     #CCGCTCGGCG  1500TGCTCAA GGCCGGCGTC GCCGACCCGG TGAAGGTCAC                     #CGTCGCCGAC  1560CGTCCAT CGCGGCTCTG TTCCTCACCA CCGAGGCCGT                     #CGGTATGGAC  1620CGTCCGC ACCCGCGGGC GACCCGACCG GTGGCATGGG                     #         1626                                                                - (2) INFORMATION FOR SEQ ID NO:160:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 541 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:160:                               #Ala Arg Arg Gly Leu Glula Tyr Asp Glu Glu                                    #                 15                                                          #Lys Val Thr Leu Gly Proeu Ala Asp Ala Val                                    #             30                                                              #Trp Gly Ala Pro Thr Ileal Leu Glu Lys Lys                                    #         45                                                                  #Ile Glu Leu Glu Asp Proer Ile Ala Lys Glu                                    #     60                                                                      #Glu Val Ala Lys Lys Thrla Glu Leu Val Lys                                    # 80                                                                          #Ala Thr Val Leu Ala Glnsp Gly Thr Thr Thr                                    #                 95                                                          #Ala Ala Gly Ala Asn Proly Leu Arg Asn Val                                    #            110                                                              #Val Glu Ala Val Thr Glnly Ile Glu Lys Ala                                    #        125                                                                  #Thr Lys Glu Gln Ile Serla Lys Glu Val Glu                                    #    140                                                                      #Gln Ile Gly Glu Leu Ileer Ala Gly Asp Thr                                    #160                                                                          #Gly Val Ile Thr Val Gluys Val Gly Asn Glu                                    #                175                                                          #Leu Thr Glu Gly Met Argly Leu Gln Leu Glu                                    #            190                                                              #Val Thr Asp Ala Glu Argle Ser Gly Tyr Phe                                    #        205                                                                  #Leu Leu Val Ser Ser Lyslu Asp Pro Tyr Ile                                    #    220                                                                      #Leu Glu Lys Val Ile Glnsp Leu Leu Pro Leu                                    #240                                                                          #Asp Val Glu Gly Glu Alaeu Ile Ile Ala Glu                                    #                255                                                          #Gly Thr Phe Lys Ser Valal Asn Lys Ile Arg                                    #            270                                                              #Arg Lys Ala Met Leu Glnly Phe Gly Asp Arg                                    #        285                                                                  #Val Ser Glu Arg Val Glyhr Gly Gly Gln Val                                    #    300                                                                      #Leu Gly Gln Ala Arg Lysla Asp Val Ser Leu                                    #320                                                                          #Val Glu Gly Ser Gly Aspsp Glu Thr Thr Ile                                    #                335                                                          #Ile Arg Ala Glu Ile Gluly Arg Val Ala Gln                                    #            350                                                              #Leu Gln Glu Arg Leu Alayr Asp Arg Glu Lys                                    #        365                                                                  #Ala Gly Ala Ala Thr Glual Ala Val Ile Lys                                    #    380                                                                      #Glu Asp Ala Val Arg Asnrg Lys His Arg Ile                                    #400                                                                          #Ala Gly Gly Gly Val Alalu Glu Gly Ile Val                                    #                415                                                          #Leu Gly Leu Thr Gly Aspro Ala Leu Asp Asp                                    #            430                                                              #Ala Leu Ser Ala Pro Leusn Ile Val Arg Val                                    #        445                                                                  #Pro Gly Val Val Ala Glusn Gly Gly Leu Glu                                    #    460                                                                      #Leu Asn Ala Ala Thr Glyro Ala Gly His Gly                                    #480                                                                          #Ala Asp Pro Val Lys Valeu Lys Ala Gly Val                                    #                495                                                          #Ile Ala Ala Leu Phe Leuln Asn Ala Ala Ser                                    #            510                                                              #Glu Lys Ala Ser Ala Proal Ala Asp Lys Pro                                    #        525                                                                  #Met Asp Phesp Pro Thr Gly Gly Met Gly Gly                                    #    540                                                                      - (2) INFORMATION FOR SEQ ID NO:161:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 985 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:161:                               #TGCTCCCGCT    60CTGCTGG TCAGCTCCAA GGTGTCGACC GTCAAGGATC                     #ACGTCGAGGG   120ATCCAGG CCGGCAAGCC GCTGCTGATC ATCGCCGAGG                     #CCGTCGCCGT   180ACGCTGG TGGTCAACAA GATCCGCGGC ACCTTCAAGT                     #CCATCCTCAC   240TTCGGTG ACCGCCGCAA GGCGATGCTG CAGGACATGG                     #ACGTCTCGCT   300GTCAGCG AAAGAGTCGG GCTGTCCCTG GAGACCGCCG                     #TCGAGGGCTC   360CGCAAGG TCGTCGTCAC CAAGGACGAG ACCACCATCG                     #TCGAGAACAG   420GCCATCG CCGGCCGGGT GGCTCAGATC CGCGCCGAGA                     #CCGGCGGTGT   480GACCGCG AGAAGCTGCA GGAGCGCCTG GCCAAGCTGG                     #AGCACCGCAT   540GCCGGAG CTGCCACCGA GGTGGAGCTC AAGGAGCGCA                     #CCGGTGGCGG   600CGCAACG CGAAGGCTGC CGTCGAAGAG GGCATCGTCG                     #GCGACGAGGC   660CAGTCGG CTCCTGCGCT GGACGACCTC GGCCTGACGG                     #TCGCCTTCAA   720ATCGTCC GCGTGGCGCT GTCGGCTCCG CTCAAGCAGA                     #CGGGTCACGG   780CCCGGCG TCGTTGCCGA GAAGGTGTCC AACCTGCCCG                     #CCGACCCGGT   840ACCGGTG AGTACGAGGA CCTGCTCAAG GCCGGCGTCG                     #TCCTCACCAC   900TCGGCGC TGCAGAACGC GGCGTCCATC GCGGCTCTGT                     #ACCCGACCGG   960GCCGACA AGCCGGAGAA GGCGTCCGCA CCCGCGGGCG                     #              985 GGACT TCTAA                                                - (2) INFORMATION FOR SEQ ID NO:162:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 327 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:162:                               #Val Ser Thr Val Lys Aspeu Val Ser Ser Lys                                    #                 15                                                          #Ala Gly Lys Pro Leu Leulu Lys Val Ile Gln                                    #             30                                                              #Leu Ser Thr Leu Val Valal Glu Gly Glu Ala                                    #         45                                                                  #Ala Val Lys Ala Pro Glyhr Phe Lys Ser Val                                    #     60                                                                      #Asp Met Ala Ile Leu Thrys Ala Met Leu Gln                                    # 80                                                                          #Leu Ser Leu Glu Thr Alaer Glu Arg Val Gly                                    #                 95                                                          #Val Val Val Thr Lys Asply Gln Ala Arg Lys                                    #            110                                                              #Ser Asp Ala Ile Ala Glylu Gly Ser Gly Asp                                    #        125                                                                  #Asn Ser Asp Ser Asp Tyrrg Ala Glu Ile Glu                                    #    140                                                                      #Lys Leu Ala Gly Gly Valln Glu Arg Leu Ala                                    #160                                                                          #Val Glu Leu Lys Glu Argly Ala Ala Thr Glu                                    #                175                                                          #Ala Lys Ala Ala Val Glusp Ala Val Arg Asn                                    #            190                                                              #Leu Leu Gln Ser Ala Proly Gly Gly Val Ala                                    #        205                                                                  #Glu Ala Thr Gly Ala Asnly Leu Thr Gly Asp                                    #    220                                                                      #Lys Gln Ile Ala Phe Asneu Ser Ala Pro Leu                                    #240                                                                          #Lys Val Ser Asn Leu Proly Val Val Ala Glu                                    #                255                                                          #Glu Tyr Glu Asp Leu Leusn Ala Ala Thr Gly                                    #            270                                                              #Thr Arg Ser Ala Leu Glnsp Pro Val Lys Val                                    #        285                                                                  #Thr Thr Glu Ala Val Valla Ala Leu Phe Leu                                    #    300                                                                      #Ala Gly Asp Pro Thr Glyys Ala Ser Ala Pro                                    #320                                                                          -  Gly Met Gly Gly Met Asp Phe                                                                 325                                                          - (2) INFORMATION FOR SEQ ID NO:163:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 403 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:163:                               #GGACGGCCGA    60CGGCTGG TGACGACCAA GTACAACCCG GCCCGCACCT                     #GCCCCGGCGG   120ATCGGCG GCGCGTACCT GTGCATCTAC GGGATGGAGG                     #CGGCGCCGTT   180GGCCGCA CCACCCAGGT GTGGAGTCGT TACCGCCACA                     #ATCCGGTGTC   240CCCTGGC TGCTGCGGTT TTTCGACCGA ATTTCGTGGT                     #CGGTCGACAT   300CTGGAAT TGCGAGCCGA CATGGCCGCA GGCCGGGGCT                     #ACGCCGACGA   360TTCTCCC TCGCCGAGCA CGAACGGTTC CTGGCCGACA                     #403               TTCCC GGCAGGCGGC CGCGTTCTCC GCC                            - (2) INFORMATION FOR SEQ ID NO:164:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 336 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:164:                               #GTCGAAGGCC    60CGGCCGC CGGCGAGTTC GACCGCGCCG AGAAAGCCGC                     #GACGCTCCGT   120CCGGGGA CCTGGTGCTC TACGACGGTG CGAGCGGGTC                     #GCCGGACAGC   180GTGGAAG GTCGACGTCG CCGTCGGTGA CCGGGTGGTG                     #GCCGACGGGG   240GGAGGCG ATGAAGATGG AGACCGTGCT GCGCGCCCCG                     #CCACTGGTCG   300CCTGGTC TCCGCTGGGC ATCTCGTCGA TCCCGGCACC                     #      336         TGCGC GCATGAGCGC CGTCGA                                    - (2) INFORMATION FOR SEQ ID NO:165:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 134 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:165:                               #Tyr Asn Pro Ala Arg Threu Val Thr Thr Lys                                    #                 15                                                          #Gly Ala Tyr Leu Cys Ileer Val Gly Ile Gly                                    #             30                                                              #Phe Val Gly Arg Thr Thrro Gly Gly Tyr Gln                                    #         45                                                                  #Pro Phe Glu Pro Gly Seryr Arg His Thr Ala                                    #     60                                                                      #Ser Trp Tyr Pro Val Serhe Phe Asp Arg Ile                                    # 80                                                                          #Met Ala Ala Gly Arg Glylu Leu Arg Ala Asp                                    #                 95                                                          #Leu Ala Glu His Glu Argsp Gly Val Phe Ser                                    #            110                                                              #Ala Phe Arg Ser Arg Glnla Asp Asp Ile Ala                                    #        125                                                                  -  Ala Ala Ala Phe Ser Ala                                                         130                                                                      - (2) INFORMATION FOR SEQ ID NO:166:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 108 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:166:                               #Asp Arg Ala Glu Lys Alala Ala Gly Glu Phe                                    #                 15                                                          #Asp Leu Val Leu Tyr Aspsp Ala Asp Thr Gly                                    #             30                                                              #Ser Ser Val Trp Lys Valsp Ala Pro Phe Ala                                    #         45                                                                  #Gly Gln Pro Leu Leu Alasp Arg Val Val Ala                                    #     60                                                                      #Arg Ala Pro Ala Asp Glyet Glu Thr Val Leu                                    # 80                                                                          #His Leu Val Asp Pro Glyeu Val Ser Ala Gly                                    #                 95                                                          #Arg Alaro Leu Val Val Val Gly Thr Gly Val                                    #            105                                                              - (2) INFORMATION FOR SEQ ID NO:167:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 31 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:167:                               #          31      CAGTG GGACCTCGAG C                                         - (2) INFORMATION FOR SEQ ID NO:168:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 27 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:168:                               #             27   CGTCA GCCGCCG                                              - (2) INFORMATION FOR SEQ ID NO:169:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 1111 base                                                         (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:169:                               #GCGGCGCCCT    60ACCTCGA GCACCACGTC ACAGGACAGC GGCCCCGCCA                     #TCCAGACCGC   120TGGCCGC TCTATATGGC CGACGGTTTC ATCGCAGCGT                     #GGTTCGCCAA   180GTCGACT ACAAAGAAGA CTTCAACGAC AACGAGCAGT                     #TCCCCACCGA   240TTGTCGC GCAAGCAGGA CATAGGCGCC GACCTGGTGA                     #AAGCCGGCGT   300CGCGTCA AGGGCCTGGG ATGGCTCAAT GAGATCAGCG                     #AGGGCCGCAA   360AATCTGC GTCAGGACCT GTTGGACTCG AGCATCGACG                     #CAGCCACCGG   420TACATGA CCGGCATGGT CGGTCTCGCC TACAACAAGG                     #GCGTCAGTCT   480ACCATCG ACGACCTCTG GGATCCCGCG TTCAAGGGCC                     #ACTCGCCGGA   540CAGGACG GCCTCGGCAT GATCATGCTC TCGCAGGGCA                     #AGAACGACAG   600GAGTCCA TTCAGCAGGC GGTCGATCTG GTCCGCGAAC                     #GCAGAAACAT   660TCGCTTC ACCGGCAACG ACTACGCCGA CGACCTGGCC                     #ACCCCGATCT   720GCGTACT CCGGTGACGT CGTGCAGCTG CAGGCGGACA                     #TGATCCCGTA   780CCCGAAT CCGGCGGCGA CTGGTTCGTC GACACGATGG                     #ACCGAGCCAA   840CAGAAGG CCGCCGAGGC GTGGATCGAC TACATCTACG                     #TGACCGACGA   900GTCGCGT TCACCCAGTT CGTGCCCGCA CTCTCGGACA                     #CGGCCGAGGT   960GATCCTG CATCGGCGGA GAACCCGCTG ATCAACCCGT                     #AGTTCAACAC  1020AAGTCGT GGGCGGCACT GACCGACGAG CAGACGCAGG                     #GGGGCATAAA  1080GTCACCG GCGGCTGACG CGGTGGTAGT GCCGATGCGA                     #        1111      GAGGA GCATAAATGG C                                         - (2) INFORMATION FOR SEQ ID NO:170:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 348 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:170:                               #Gln Asp Ser Gly Pro Alaer Ser Thr Thr Ser                                    #                 15                                                          #Leu Tyr Met Ala Asp Glyal Ser Asn Trp Pro                                    #             30                                                              #Ile Thr Val Asp Tyr Lysln Thr Ala Ser Gly                                    #         45                                                                  #Ala Lys Val Lys Glu Prosn Glu Gln Trp Phe                                    #     60                                                                      #Leu Val Ile Pro Thr Glusp Ile Gly Ala Asp                                    # 80                                                                          #Trp Leu Asn Glu Ile Seral Lys Gly Leu Gly                                    #                 95                                                          #Arg Gln Asp Leu Leu Aspsn Arg Lys Asn Leu                                    #            110                                                              #Ala Pro Tyr Met Thr Glyly Arg Lys Phe Thr                                    #        125                                                                  #Thr Gly Arg Asp Ile Argyr Asn Lys Ala Ala                                    #    140                                                                      #Lys Gly Arg Val Ser Leurp Asp Pro Ala Phe                                    #160                                                                          #Ile Met Leu Ser Gln Glysp Gly Leu Gly Met                                    #                175                                                          #Ile Gln Gln Ala Val Aspro Thr Thr Glu Ser                                    #            190                                                              #Ile Arg Arg Phe Thr Glysn Asp Arg Gly Gln                                    #        205                                                                  #Asn Ile Ala Ile Ala Glnsp Leu Ala Ala Gly                                    #    220                                                                      #Ala Asp Asn Pro Asp Leual Val Gln Leu Gln                                    #240                                                                          #Trp Phe Val Asp Thr Metlu Ser Gly Gly Asp                                    #                255                                                          #Ala Ala Glu Ala Trp Ilehr Gln Asn Gln Lys                                    #            270                                                              #Lys Leu Val Ala Phe Thrrg Ala Asn Tyr Ala                                    #        285                                                                  #Asp Glu Leu Ala Lys Valeu Ser Asp Met Thr                                    #    300                                                                      #Asn Pro Ser Ala Glu Vallu Asn Pro Leu Ile                                    #320                                                                          #Thr Asp Glu Gln Thr Glner Trp Ala Ala Leu                                    #                335                                                          #Gly Glyhe Asn Thr Ala Tyr Ala Ala Val Thr                                    #            345                                                              - (2) INFORMATION FOR SEQ ID NO:171:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 1420 base                                                         (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:171:                               #CGGTCGGGTT    60CTGAACT CGACCTGGTT GGCCTGGGCC GTCGCGGTCG                     #GCGGCAGCGC   120GTCGTGC TGACCGAGGT GCACAACGCG TTGCGTCGGC                     #CGTTGCTGCT   180GTGCAAC TCCTGCGTAC CTACATCCTG CCGCTGGGCG                     #TGGTCGCCAC   240GCGATGG AGATCTCCGA CGACGCCACG TCGGTACGGT                     #CCCTCATCCA   300GTGTTGT TGACGTTGGT GCTGTCCGGG CTCAACGCCA                     #ACGTCGCGCG   360GACAGCT GGCGCAGGCG GATTCCGTCG ATCTTCCTCG                     #GCGCGAACGT   420GCGGTCG GTATCACCGT GATCATGGCC TATGTCTGGG                     #CTCTGCAGAA   480ACCGCAC TGGGCGTCAC TTCCATCGTT CTTGGCCTGG                     #TCCGGCTCGG   540ATCATCT CGGGTCTGCT GCTGCTGTTC GAGCAACCGT                     #GCGTGGTGGA   600GTCCCCA CCGCGGCGGG CCGGCCGTCC GCCCACGGCC                     #TGCCCAACGC   660GCAACAC ATATCGACAC CGGCGGCAAC CTGCTGGTAA                     #ACCGGCTGAC   720GCGTCGT TCACCAATTA CAGCCGGCCC GTGGGAGAGC                     #TGCTGTCGTC   780TTCAACG CCGCGGACAC CCCCGATGAT GTCTGCGAGA                     #TCTATCTCGG   840CTGCCCG AACTGCGCAC CGACGGACAG ATCGCCACGC                     #ACTCGGTCAG   900GAGAAGT CGATCCCGTT GCACACACCC GCGGTGGACG                     #GCCTNAACGG   960CGATGGG TCTGGTACGC CGCGCGCCGG CAGGAACTTC                     #CTGTGGCGTC  1020TTCGACA CGCCGGAACG GATCGCCTCG GCCATGCGGG                     #GTCTGGTCCG  1080GCAGACG ACGAACAGCA GGAGATCGCC GACGTGGTGC                     #TGAGGTTCAT  1140GAACGCC TCCAGCAGCC GGGTCAGGTA CCGACCGGGA                     #TCCCGGCGCG  1200GTGAGTC TGTCCGTGAT CGATCAGGAC GGCGACGTGA                     #CGGTACTGGC  1260GGCGACT TCCTGGGGCA GACCACGCTG ACGCGGGAAC                     #AGATCGAGCG  1320CTGGAGG AAGTCACCGT GCTGGAGATG GCCCGTGACG                     #CCGACCGGCG  1380AAGCCGA TCCTGCTGCA CGTGATCGGG GCCGTGATCG                     #  1420            GTTGA TGGCGGACTC GCAGGACTGA                                - (2) INFORMATION FOR SEQ ID NO:172:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 471 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:172:                               #Ala Trp Ala Val Ala Valsn Ser Thr Trp Leu                                    #                 15                                                          #Leu Thr Glu Val His Asnal Leu Leu Val Val                                    #             30                                                              #Arg Pro Val Gln Leu Leuly Ser Ala Leu Ala                                    #         45                                                                  #Leu Leu Leu Leu Val Glnro Leu Gly Ala Leu                                    #     60                                                                      #Val Arg Leu Val Ala Thrsp Asp Ala Thr Ser                                    # 80                                                                          #Leu Ser Gly Leu Asn Alaeu Leu Thr Leu Val                                    #                 95                                                          #Trp Arg Arg Arg Ile Prola Pro Glu Asp Ser                                    #            110                                                              #Leu Ile Ala Val Gly Ileal Ala Arg Phe Ala                                    #        125                                                                  #Asn Val Gly Gly Leu Pheyr Val Trp Gly Ala                                    #    140                                                                      #Gly Leu Ala Leu Gln Asnhr Ser Ile Val Leu                                    #160                                                                          #Leu Leu Phe Glu Gln Prole Ser Gly Leu Leu                                    #                175                                                          #Thr Ala Ala Gly Arg Prorp Ile Thr Val Pro                                    #            190                                                              #Trp Arg Ala Thr His Ileal Val Glu Val Asn                                    #        205                                                                  #Asn Ala Glu Leu Ala Glyeu Leu Val Met Pro                                    #    220                                                                      #Gly Glu His Arg Leu Thryr Ser Arg Pro Val                                    #240                                                                          #Pro Asp Asp Val Cys Glusn Ala Ala Asp Thr                                    #                255                                                          #Glu Leu Arg Thr Asp Glyla Ala Ser Leu Pro                                    #            270                                                              #Glu Tyr Glu Lys Ser Ileyr Leu Gly Ala Ala                                    #        285                                                                  #Val Arg Ser Thr Tyr Leula Val Asp Asp Ser                                    #    300                                                                      #Glu Leu Arg Xaa Asn Glyla Ala Arg Arg Gln                                    #320                                                                          #Ile Ala Ser Ala Met Argsp Thr Pro Glu Arg                                    #                335                                                          #Asp Glu Gln Gln Glu Ileeu Arg Leu Ala Asp                                    #            350                                                              #Asn Gly Glu Arg Leu Glneu Val Arg Tyr Gly                                    #        365                                                                  #Phe Ile Val Asp Gly Argro Thr Gly Met Arg                                    #    380                                                                      #Asp Val Ile Pro Ala Argle Asp Gln Asp Gly                                    #400                                                                          #Thr Thr Leu Thr Arg Glusp Phe Leu Gly Gln                                    #                415                                                          #Glu Val Thr Val Leu Glula His Ala Leu Glu                                    #            430                                                              #His Arg Lys Pro Ile Leule Glu Arg Leu Val                                    #        445                                                                  #Arg Arg Ala His Glu Leula Val Ile Ala Asp                                    #    460                                                                      -  Arg Leu Met Asp Ser Gln Asp                                                #470                                                                          - (2) INFORMATION FOR SEQ ID NO:173:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 2172 base                                                         (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:173:                               #AAAAAGACGC    60TGCCCTG GAATGCGCGA ACGTCTGAAC ACCCGACGCG                     #GATGCTGCTT   120TCCTGTC GCGGATGAGC ATCCAGTCCA AGTTGCTGCT                     #CGGACGGTCC   180TCTCGGC TGCGGTGGTC GGTTTCATCG GCTATCAGTC                     #GTCGCGCGGG   240CGGTGTT CGACCGCCTC ACCGACATCC GCGAGTCGCA                     #CGGCAGCACT   300TCGCGGA CCTGAAGAAC TCGATGGTGA TTTACTCGCG                     #TGCGACGATC   360TCGGCGC GTTCAGCGAC GGTTTCCGTC AGCTCGGCGA                     #CAACACCACC   420CGGCGTC ATTGCGCCGT TACTACGACC GGACGTTCGC                     #CAACCCCCAG   480GAAACCG CGTCGACGTC CGCGCGCTCA TCCCGAAATC                     #GATCGCGTTC   540CGCTCTA TACCCCGCCG TTTCAGAACT GGGAGAAGGC                     #CGAGTTCTTC   600ACGGCAG CGCCTGGTCG GCCGCCAATG CCAGATTCAA                     #CGAGGGCAAC   660ACCGCTT CAACTTCGAG GATCTGATGC TGCTCGACCT                     #CGGCCCCTAT   720CCTACAA GGGGCCGGAT CTCGGGACAA ACATCGTCAA                     #GATCGACTAT   780TGTCGGA AGCCTACGAG AAGGCGGTCG CGTCGAACTC                     #CTGGTTCCTG   840ACTTCGG GTGGTACCTG CCTGCCGAGG AACCGACCGC                     #CCCGATCGCG   900TGAAGGA CCGAGTCGAC GGTGTGATGG CGGTCCAGTT                     #GGGAGACACC   960TGATGAC GGCGCGGGGA CAGTGGCGTG ACACCGGGAT                     #GCTGTTCCGC  1020TGGTCGG ACCGGACAAT CTGATGCGCT CGGACTCCCG                     #GGAGGTCGCC  1080AGTTCCT GGCCGACGTC GTCGAGGGGG GAACCCCGCC                     #CCGCTCCGTC  1140ACCGCCG CGGCACCACG CTGGTGCAGC CGGTGACCAC                     #CGGCCACGAG  1200GCGGCAA CACCGGGACG ACGATCGAGG ACGACTATCT                     #CGTGGCCAAG  1260ACTCACC GGTGGACCTG CCGGGACTGC ACTGGGTGAT                     #GGTGCTGTCG  1320AGGCGTT CGCCCCGGTG GCGCAGTTCA CCAGGACCCT                     #GTTGTTCGTC  1380TCTTCGG CGTGTCGCTG GCGGCCATGC TGCTGGCGCG                     #CTACCGCCTC  1440GGTTGCA GGCCGGCGCC CAGCAGATCA GCGGCGGTGA                     #CAACGACATG  1500TGTCTCG TGACGAATTC GGCGATCTGA CAACAGCTTT                     #GAACCAACGG  1560CGATCAA GGACGAGCTG CTCGGCGAGG AGCGCGCCGA                     #GGAGGAGACG  1620TGATGCC CGAACCGGTG ATGCAGCGCT ACCTCGACGG                     #CCTCGACGAG  1680ACAAGAA CGTCACGGTG ATCTTCGCCG ACATGATGGG                     #GACCCGCCAG  1740TGACCTC CGAGGAACTG ATGGTGGTGG TCAACGACCT                     #CGACGGGTAC  1800CCGAGAG TCTCGGGGTC GACCACGTGC GGACGCTGCA                     #GGTCAATTTC  1860GGTTAGG CGTGCCGCGG CTGGACAACG TCCGGCGCAC                     #CGACCTGCGG  1920ACCGCAT CATCGACCGG CACGCCGCCG AGTCCGGGCA                     #GTCCACGTTG  1980TCGACAC CGGGTCGGCG GCCAGCGGGC TGGTGGGGCG                     #CGGCTCCCCC  2040GGGGTTC GGCGGTCGAT GTCGCTAACC AGGTGCAGCG                     #TCTCGACTTC  2100ACGTCAC CTCGCGGGTG CACGAGGTCA TGCAGGAAAC                     #GTTGCAGGGC  2160AGGTCGT CGGCGAGCGC GGCGTCGAGA CGGTCTGGCG                     #     2172                                                                    - (2) INFORMATION FOR SEQ ID NO:174:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 722 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:174:                               #Ser Glu His Pro Thr Argrp Asn Ala Arg Thr                                    #                 15                                                          #Arg Met Ser Ile Gln Seryr His Leu Leu Ser                                    #             30                                                              #Ile Leu Ser Ala Ala Valeu Leu Leu Thr Ser                                    #         45                                                                  #Ser Ser Leu Arg Ala Seryr Gln Ser Gly Arg                                    #     60                                                                      #Ser Gln Ser Arg Gly Leuhr Asp Ile Arg Glu                                    # 80                                                                          #Met Val Ile Tyr Ser Argsp Leu Lys Asn Ser                                    #                 95                                                          #Phe Ser Asp Gly Phe Arglu Ala Ile Gly Ala                                    #            110                                                              #Gln Ala Ala Ser Leu Arghr Ile Asn Thr Gly                                    #        125                                                                  #Thr Leu Asp Asp Ser Glyhr Phe Ala Asn Thr                                    #    140                                                                      #Lys Ser Asn Pro Gln Argrg Ala Leu Ile Pro                                    #160                                                                          #Gln Asn Trp Glu Lys Alayr Thr Pro Pro Phe                                    #                175                                                          #Ala Trp Ser Ala Ala Asnla Arg Asp Gly Ser                                    #            190                                                              #Val His Arg Phe Asn Phehe Phe Arg Glu Ile                                    #        205                                                                  #Asn Val Val Tyr Ser Alaeu Asp Leu Glu Gly                                    #    220                                                                      #Val Asn Gly Pro Tyr Argeu Gly Thr Asn Ile                                    #240                                                                          #Ala Val Ala Ser Asn Serlu Ala Tyr Glu Lys                                    #                255                                                          #Trp Tyr Leu Pro Ala Glual Thr Asp Phe Gly                                    #            270                                                              #Gly Leu Lys Asp Arg Valhe Leu Ser Pro Val                                    #        285                                                                  #Ala Arg Ile Asn Glu Leual Gln Phe Pro Ile                                    #    300                                                                      #Gly Met Gly Asp Thr Glyln Trp Arg Asp Thr                                    #320                                                                          #Met Arg Ser Asp Ser Argly Pro Asp Asn Leu                                    #                335                                                          #Ala Asp Val Val Glu Glyrg Glu Lys Phe Leu                                    #            350                                                              #Val Asp Arg Arg Gly Thral Ala Asp Glu Ser                                    #        365                                                                  #Val Glu Glu Ala Gln Argal Thr Thr Arg Ser                                    #    380                                                                      #Tyr Leu Gly His Glu Alahr Ile Glu Asp Asp                                    #400                                                                          #Gly Leu His Trp Val Ilero Val Asp Leu Pro                                    #                415                                                          #Ala Pro Val Ala Gln Phehr Asp Glu Ala Phe                                    #            430                                                              #Ile Ile Phe Gly Val Sereu Ser Thr Val Ile                                    #        445                                                                  #Val Arg Pro Ile Arg Argeu Ala Arg Leu Phe                                    #    460                                                                      #Gly Asp Tyr Arg Leu Alaln Gln Ile Ser Gly                                    #480                                                                          #Asp Leu Thr Thr Ala Pherg Asp Glu Phe Gly                                    #                495                                                          #Asp Glu Leu Leu Gly Glusn Leu Ser Ile Lys                                    #            510                                                              #Ser Leu Met Pro Glu Proln Arg Leu Met Leu                                    #        525                                                                  #Thr Ile Ala Gln Asp Hiseu Asp Gly Glu Glu                                    #    540                                                                      #Met Gly Leu Asp Glu Leule Phe Ala Asp Met                                    #560                                                                          #Val Val Val Asn Asp Leuer Glu Glu Leu Met                                    #                575                                                          #Leu Gly Val Asp His Valla Ala Ala Glu Ser                                    #            590                                                              #Cys Gly Leu Gly Val Proly Tyr Leu Ala Ser                                    #        605                                                                  #Phe Ala Ile Glu Met Asprg Arg Thr Val Asn                                    #    620                                                                      #Gly His Asp Leu Arg Leuis Ala Ala Glu Ser                                    #640                                                                          #Ser Gly Leu Val Gly Arghr Gly Ser Ala Ala                                    #                655                                                          #Ala Val Asp Val Ala Asnsp Met Trp Gly Ser                                    #            670                                                              #Ile Tyr Val Thr Ser Arger Pro Gln Pro Gly                                    #        685                                                                  #Phe Val Ala Ala Gly Gluln Glu Thr Leu Asp                                    #    700                                                                      #Trp Arg Leu Gln Gly Hisly Val Glu Thr Val                                    #720                                                                          -  Arg Arg                                                                    - (2) INFORMATION FOR SEQ ID NO:175:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 898 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:175:                               #CCGGCCGTCC    60GGCTCGG CGACTGGATC ACCGTCCCCA CCGCGGCGGG                     #CGGCGGCAAC   120TGGTGGA AGTCAACTGG CGTGCAACAC ATATCGACAC                     #CAGCCGGCCC   180CCAACGC CGAACTCGCC GGCGCGTCGT TCACCAATTA                     #CCCCGATGAT   240GGCTGAC CGTCGTCACC ACCTTCAACG CCGCGGACAC                     #CGACGGACAG   300TGTCGTC GGTCGCGGCG TCGCTGCCCG AACTGCGCAC                     #GCACACACCC   360ATCTCGG TGCGGCCGAA TACGAGAAGT CGATCCCGTT                     #CGCGCGCCGG   420CGGTCAG GAGCACGTAC CTGCGATGGG TCTGGTACGC                     #TCGCCTCGGC   480TAACGGC GTCGCCGACG ATTCGACACG CCGGAACGGA                     #AGATCGCCGA   540GCGTCCA CACTGCGCTT GGCAGACGAC GAACAGCAGG                     #GTCAGGTACC   600GTCCGTT ACGGCAACGG GGAACGCCTC CAGCAGCCGG                     #ATCAGGACGG   660TTCATCG TAGACGGCAG GGTGAGTCTG TCCGTGATCG                     #CCACGCTGAC   720GCGCGGG TGCTCGAGCG TGGCGACTTC CTGGGGCAGA                     #TGGAGATGGC   780CTGGCGA CCGCGCACGC GCTGGAGGAA GTCACCGTGC                     #TGATCGGGGC   840GAGCGCC TGGTGCACCG AAAGCCGATC CTGCTGCACG                     #AGGACTGA     898CGGCGCG CGCACGAACT TCGGTTGATG GCGGACTCGC                     - (2) INFORMATION FOR SEQ ID NO:176:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 2013 base                                                         (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:176:                               #CACCGACATC    60GACGGTC CTCGCTGCGC GCATCGGTGT TCGACCGCCT                     #CTCGATGGTG   120CGCGCGG GTTGGAGAAT CAGTTCGCGG ACCTGAAGAA                     #CGGTTTCCGT   180GCAGCAC TGCCACGGAG GCGATCGGCG CGTTCAGCGA                     #TTACTACGAC   240CGACGAT CAATACCGGG CAGGCGGCGT CATTGCGCCG                     #CCGCGCGCTC   300ACACCAC CCTCGACGAC AGCGGAAACC GCGTCGACGT                     #GTTTCAGAAC   360ACCCCCA GCGCTATCTG CAGGCGCTCT ATACCCCGCC                     #GGCCGCCAAT   420TCGCGTT CGACGACGCG CGCGACGGCA GCGCCTGGTC                     #GGATCTGATG   480AGTTCTT CCGCGAGATC GTGCACCGCT TCAACTTCGA                     #TCTCGGGACA   540AGGGCAA CGTGGTGTAC TCCGCCTACA AGGGGCCGGA                     #GAAGGCGGTC   600GCCCCTA TCGCAACCGG GAACTGTCGG AAGCCTACGA                     #GCCTGCCGAG   660TCGACTA TGTCGGTGTC ACCGACTTCG GGTGGTACCT                     #CGGTGTGATG   720GGTTCCT GTCCCCGGTC GGGTTGAAGG ACCGAGTCGA                     #ACAGTGGCGT   780CGATCGC GCGGATCAAC GAATTGATGA CGGCGCGGGG                     #TCTGATGCGC   840GAGACAC CGGTGAGACC ATCCTGGTCG GACCGGACAA                     #CGTCGAGGGG   900TGTTCCG CGAGAACCGG GAGAAGTTCC TGGCCGACGT                     #GCTGGTGCAG   960AGGTCGC CGACGAATCG GTTGACCGCC GCGGCACCAC                     #GACGATCGAG  1020GCTCCGT CGAGGAGGCC CAACGCGGCA ACACCGGGAC                     #GCCGGGACTG  1080GCCACGA GGCGTTACAG GCGTACTCAC CGGTGGACCT                     #GGCGCAGTTC  1140TGGCCAA GATCGACACC GACGAGGCGT TCGCCCCGGT                     #GGCGGCCATG  1200TGCTGTC GACGGTGATC ATCATCTTCG GCGTGTCGCT                     #CCAGCAGATC  1260TGTTCGT CCGTCCGATC CGGCGGTTGC AGGCCGGCGC                     #CGGCGATCTG  1320ACCGCCT CGCTCTGCCG GTGTTGTCTC GTGACGAATT                     #GCTCGGCGAG  1380ACGACAT GAGTCGCAAT CTGTCGATCA AGGACGAGCT                     #GATGCAGCGC  1440ACCAACG GCTGATGCTG TCCCTGATGC CCGAACCGGT                     #GATCTTCGCC  1500AGGAGAC GATCGCCCAG GACCACAAGA ACGTCACGGT                     #GATGGTGGTG  1560TCGACGA GTTGTCGCGC ATGTTGACCT CCGAGGAACT                     #CGACCACGTG  1620CCCGCCA GTTCGACGCC GCCGCCGAGA GTCTCGGGGT                     #GCTGGACAAC  1680ACGGGTA CCTGGCCAGC TGCGGGTTAG GCGTGCCGCG                     #GCACGCCGCC  1740TCAATTT CGCGATCGAA ATGGACCGCA TCATCGACCG                     #GGCCAGCGGG  1800ACCTGCG GCTCCGCGCG GGCATCGACA CCGGGTCGGC                     #TGTCGCTAAC  1860CCACGTT GGCGTACGAC ATGTGGGGTT CGGCGGTCGA                     #GCACGAGGTC  1920GCTCCCC CCAGCCCGGC ATCTACGTCA CCTCGCGGGT                     #CGGCGTCGAG  1980TCGACTT CGTCGCCGCC GGGGAGGTCG TCGGCGAGCG                     #       2013       CAGGG CCACCGGCGA TGA                                       - (2) INFORMATION FOR SEQ ID NO:177:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 297 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:177:                               #Thr Val Pro Thr Ala Alaeu Gly Asp Trp Ile                                    #                 15                                                          #Glu Val Asn Trp Arg Alais Gly Arg Val Val                                    #             30                                                              #Val Met Pro Asn Ala Gluly Gly Asn Leu Leu                                    #         45                                                                  #Arg Pro Val Gly Glu Hishe Thr Asn Tyr Ser                                    #     60                                                                      #Ala Asp Thr Pro Asp Asphr Thr Phe Asn Ala                                    # 80                                                                          #Ser Leu Pro Glu Leu Arger Ser Val Ala Ala                                    #                 95                                                          #Gly Ala Ala Glu Tyr Glula Thr Leu Tyr Leu                                    #            110                                                              #Asp Asp Ser Val Arg Seris Thr Pro Ala Val                                    #        125                                                                  #Arg Arg Gln Glu Leu Argal Trp Tyr Ala Ala                                    #    140                                                                      #Pro Glu Arg Ile Ala Sersp Xaa Phe Asp Thr                                    #160                                                                          #Leu Ala Asp Asp Glu Glnla Ser Thr Leu Arg                                    #                175                                                          #Arg Tyr Gly Asn Gly Glual Val Arg Leu Val                                    #            190                                                              #Gly Met Arg Phe Ile Vally Gln Val Pro Thr                                    #        205                                                                  #Gln Asp Gly Asp Val Ileeu Ser Val Ile Asp                                    #    220                                                                      #Leu Gly Gln Thr Thr Leulu Arg Gly Asp Phe                                    #240                                                                          #Ala Leu Glu Glu Val Threu Ala Thr Ala His                                    #                255                                                          #Arg Leu Val His Arg Lysrg Asp Glu Ile Glu                                    #            270                                                              #Ala Asp Arg Arg Ala Hisal Ile Gly Ala Val                                    #        285                                                                  -  Glu Leu Arg Leu Met Asp Ser Gln Asp                                        #    295                                                                      - (2) INFORMATION FOR SEQ ID NO:178:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 670 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:178:                               #Ala Ser Val Phe Asp Argrg Ser Ser Leu Arg                                    #                 15                                                          #Gly Leu Glu Asn Gln Phelu Ser Gln Ser Arg                                    #             30                                                              #Ser Arg Gly Ser Thr Alaer Met Val Ile Tyr                                    #         45                                                                  #Phe Arg Gln Leu Gly Aspla Phe Ser Asp Gly                                    #     60                                                                      #Leu Arg Arg Tyr Tyr Asply Gln Ala Ala Ser                                    # 80                                                                          #Ser Gly Asn Arg Val Asphr Thr Leu Asp Asp                                    #                 95                                                          #Gln Arg Tyr Leu Gln Alaro Lys Ser Asn Pro                                    #            110                                                              #Lys Ala Ile Ala Phe Asphe Gln Asn Trp Glu                                    #        125                                                                  #Ala Asn Ala Arg Phe Asner Ala Trp Ser Ala                                    #    140                                                                      #Asn Phe Glu Asp Leu Metle Val His Arg Phe                                    #160                                                                          #Ser Ala Tyr Lys Gly Proly Asn Val Val Tyr                                    #                175                                                          #Tyr Arg Asn Arg Glu Leule Val Asn Gly Pro                                    #            190                                                              #Asn Ser Ile Asp Tyr Valys Ala Val Ala Ser                                    #        205                                                                  #Ala Glu Glu Pro Thr Alaly Trp Tyr Leu Pro                                    #    220                                                                      #Arg Val Asp Gly Val Metal Gly Leu Lys Asp                                    #240                                                                          #Glu Leu Met Thr Ala Argle Ala Arg Ile Asn                                    #                255                                                          #Thr Gly Glu Thr Ile Leuhr Gly Met Gly Asp                                    #            270                                                              #Ser Arg Leu Phe Arg Glueu Met Arg Ser Asp                                    #        285                                                                  #Glu Gly Gly Thr Pro Proeu Ala Asp Val Val                                    #    300                                                                      #Gly Thr Thr Leu Val Glner Val Asp Arg Arg                                    #320                                                                          #Gln Arg Gly Asn Thr Glyer Val Glu Glu Ala                                    #                335                                                          #Glu Ala Leu Gln Ala Tyrsp Tyr Leu Gly His                                    #            350                                                              #Val Ile Val Ala Lys Ilero Gly Leu His Trp                                    #        365                                                                  #Gln Phe Thr Arg Thr Leuhe Ala Pro Val Ala                                    #    380                                                                      #Val Ser Leu Ala Ala Metle Ile Ile Phe Gly                                    #400                                                                          #Arg Arg Leu Gln Ala Glyhe Val Arg Pro Ile                                    #                415                                                          #Leu Ala Leu Pro Val Leuly Gly Asp Tyr Arg                                    #            430                                                              #Ala Phe Asn Asp Met Serly Asp Leu Thr Thr                                    #        445                                                                  #Gly Glu Glu Arg Ala Gluys Asp Glu Leu Leu                                    #    460                                                                      #Glu Pro Val Met Gln Argeu Ser Leu Met Pro                                    #480                                                                          #Asp His Lys Asn Val Thrlu Thr Ile Ala Gln                                    #                495                                                          #Glu Leu Ser Arg Met Leuet Met Gly Leu Asp                                    #            510                                                              #Asp Leu Thr Arg Gln Pheet Val Val Val Asn                                    #        525                                                                  #His Val Arg Thr Leu Hiser Leu Gly Val Asp                                    #    540                                                                      #Val Pro Arg Leu Asp Asner Cys Gly Leu Gly                                    #560                                                                          #Met Asp Arg Ile Ile Aspsn Phe Ala Ile Glu                                    #                575                                                          #Arg Leu Arg Ala Gly Ileer Gly His Asp Leu                                    #            590                                                              #Gly Arg Ser Thr Leu Alala Ser Gly Leu Val                                    #        605                                                                  #Ala Asn Gln Val Gln Arger Ala Val Asp Val                                    #    620                                                                      #Ser Arg Val His Glu Vally Ile Tyr Val Thr                                    #640                                                                          #Gly Glu Val Val Gly Glusp Phe Val Ala Ala                                    #                655                                                          #Gly His Arg Arglu Thr Val Trp Arg Leu Gln                                    #            670                                                              - (2) INFORMATION FOR SEQ ID NO:179:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 520 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:179:                               #CTCGGTGGCA    60CCCTCTT CCATGCCGAG GAGAAGATGG AGAAGGCCGT                     #CAACCGGATC   120CGTCGAT TCGTACCGGC CGCGCGAACC CCGGCATGTT                     #CAACGTGCCC   180ACGGCGC CTCCACCCCG ATCACGCAGC TGTCCAGCAT                     #CATCGAGGAT   240TGGTGAT CAAGCCCTAC GAGGCGAGCC AGCTGCGCCT                     #CATCCGGGTG   300CCGACCT CGGCGTCAAT CCGACCAACG ACGGCAACAT                     #CAAGGCCAAG   360TCACCGA GGAGCGCCGC CGCGACCTGG TCAAGCAGGC                     #CACCTTTCGC   420AGGTGTC GGTGCGCAAC ATCCGTCGCA ACGATATGAA                     #GATCGCAGGT   480GGCTGCC GACGCCACCG CCGTCGTAGA AGCGACAGAG                     #   520            GCCTT CTGTGGCGGG CCGACACCAC                                - (2) INFORMATION FOR SEQ ID NO:180:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 1071 base                                                         (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:180:                               #TCTGGCAGGT    60TGCACTC TATGAGCGAA ATCGCCCGTC CCTGGCGGGT                     #CACCACGGCG   120GCGCCGC GGGTATCGCC GGGGTGCTGA GCATCGCGGT                     #GACGCAAACC   180GCCTCCC GCAGCCCCCG CTGCCCGCCC CTGCCACAGT                     #GACGCCTGCC   240CCAACGC CGCGCCACAA CTCATCCCGC GCCCCGGTGT                     #GCCGGCCCCC   300CCGCGGT GCCCGCCGGG GTGAGCGCCC CGGCGGTCGC                     #GCTCAGCGAG   360GCCCGGT GTCCACGATC GCCCCGGCCA CCTCGGGCAC                     #CCGCGCCCTC   420AGGGCGT CACGATGGAG CCGCAGTCCA GCCGCGACTT                     #CGTGCCGGAC   480CGAAGCC GCGGGGCTGG GAGCACATCC CGGACCCGAA                     #GAACGCCCAG   540TGGCCGA CCGGGTCGGC GGCAACGGCC TGTACTCGTC                     #CCACGGCTTC   600AACTCGT CGGCGAGTTC GACCCCAAGG AAGCGATCAG                     #CGACTTCGGC   660AGCTGCC GGCGTGGCGT TCCACCGACG CGTCGCTGGC                     #GCTGAACACG   720CGCTGAT CGAGGGCACC TACCGCGAGA ACAACATGAA                     #GCTGTCGGTG   780TCATTGC CACCGCGGGG CCCGACCACT ACCTGGTGTC                     #GATTGTCAAC   840AACAGGC CGTGGCCGAA GCCGCGGAGG CCACCGACGC                     #ACCCGGTGCC   900GCGTTCC GGGTCCGGGT CCGGCCGCAC CGCCACCTGC                     #ACCACCCCCG   960CCGCCCC CGGCGCCCCG GCGCTGCCGC TGGCCGTCGC                     #GGGATAGACG  1020CCGCCGT GGCGCCCGCG CCACAGCTGC TGGGACTGCA                     #T           1071GGCGAAG CCTGGCGCCC GGGGGACGAC GGCCCCTTTC                     - (2) INFORMATION FOR SEQ ID NO:181:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 152 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:181:                               #Glu Lys Met Glu Lys Alaeu Phe His Ala Glu                                    #                 15                                                          #Ile Arg Thr Gly Arg Alasp Asp Leu Ala Ser                                    #             30                                                              #Asp Tyr Tyr Gly Ala Sersn Arg Ile Asn Ile                                    #         45                                                                  #Val Pro Glu Ala Arg Meteu Ser Ser Ile Asn                                    #     60                                                                      #Leu Arg Leu Ile Glu Aspyr Glu Ala Ser Gln                                    # 80                                                                          #Pro Thr Asn Asp Gly Asnsp Leu Gly Val Asn                                    #                 95                                                          #Glu Glu Arg Arg Arg Asple Pro Gln Leu Thr                                    #            110                                                              #Asp Ala Lys Val Ser Valys Ala Lys Gly Glu                                    #        125                                                                  #Phe Arg Ile Ala Pro Valsn Asp Met Asn Thr                                    #    140                                                                      -  Arg Leu Pro Thr Pro Pro Pro Ser                                            #150                                                                          - (2) INFORMATION FOR SEQ ID NO:182:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 331 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:182:                               #Leu Ala Gly Gly Ile Glyrg Pro Trp Arg Val                                    #                 15                                                          #Ser Ile Ala Val Thr Thrle Ala Gly Val Leu                                    #             30                                                              #Pro Leu Pro Ala Pro Alaly Leu Pro Gln Pro                                    #         45                                                                  #Asn Ala Ala Pro Gln Leual Thr Val Ala Pro                                    #     60                                                                      #Gly Gly Ala Ala Ala Valal Thr Pro Ala Thr                                    # 80                                                                          #Pro Ala Pro Ala Leu Prola Pro Ala Val Ala                                    #                 95                                                          #Thr Ser Gly Thr Leu Serhr Ile Ala Pro Ala                                    #            110                                                              #Glu Pro Gln Ser Ser Argys Gly Val Thr Met                                    #        125                                                                  #Lys Pro Arg Gly Trp Glusn Ile Val Leu Pro                                    #    140                                                                      #Phe Ala Val Leu Ala Aspsn Val Pro Asp Ala                                    #160                                                                          #Asn Ala Gln Val Val Vally Leu Tyr Ser Ser                                    #                175                                                          #Glu Ala Ile Ser His Glylu Phe Asp Pro Lys                                    #            190                                                              #Arg Ser Thr Asp Ala Serys Leu Pro Ala Trp                                    #        205                                                                  #Leu Ile Glu Gly Thr Tyrly Met Pro Ser Ser                                    #    220                                                                      #Arg Arg His Val Ile Alays Leu Asn Thr Ser                                    #240                                                                          #Leu Ser Val Thr Thr Seris Tyr Leu Val Ser                                    #                255                                                          #Ala Thr Asp Ala Ile Valla Glu Ala Ala Glu                                    #            270                                                              #Gly Pro Ala Ala Pro Proer Val Pro Gly Pro                                    #        285                                                                  #Ala Pro Gly Ala Pro Alaro Gly Val Pro Pro                                    #    300                                                                      #Pro Ala Val Pro Ala Valla Pro Pro Pro Ala                                    #320                                                                          #Glyla Pro Ala Pro Gln Leu Leu Gly Leu Gln                                    #                330                                                          - (2) INFORMATION FOR SEQ ID NO:183:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 207 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:183:                               #CATCCCGTCG    60AGAACAA GGTCACGGGC GGCCGCATCC CGCGCGAGTA                     #CCCGCTGGTT   120CGCAGGA CGCCATGCAG TACGGCGTGC TGGCCGGCTA                     #GGAAATGGCA   180CGCTGCT CGACGGTGCC TACCACGAAG TCGACTCGTC                     #            207   TCCCA GGTCATA                                              - (2) INFORMATION FOR SEQ ID NO:184:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 69 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:184:                               #Gly Arg Ile Pro Arg Glusn Lys Val Thr Gly                                    #                 15                                                          #Asp Ala Met Gln Tyr Glysp Ala Gly Ala Gln                                    #             30                                                              #Lys Leu Thr Leu Leu Aspro Leu Val Asn Val                                    #         45                                                                  #Met Ala Phe Lys Val Alaal Asp Ser Ser Glu                                    #     60                                                                      -  Gly Ser Gln Val Ile                                                         65                                                                           - (2) INFORMATION FOR SEQ ID NO:185:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 898 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:185:                               #GACGGCACAC    60GGCGTGA GGCCAACCAC TAGGCTGGTC ACCAGTAGTC                     #TGTGAACGGC   120TGAGGAC AGAGGAGACA CCCGTGACGA TCCGTGTTGG                     #CGAAGGCAAG   180GACGCAA CTTCTTCCGC GCGCTGGACG CGCAGAAGGC                     #GCTGGCGCAC   240AGATCGT CGCGGTCAAC GACCTCACCG ACAACGCCAC                     #CGAAGGCGAG   300ACTCGAT CCTGGGCCGG CTGCCCTACG ACGTGAGCCT                     #AGGCCCGGCG   360TCGGCAG CACCAAGATC AAGGCGCTCG AGGTCAAGGA                     #CATCTTCACC   420GCGACCT GGGCGTCGAC GTCGTCGTCG AGTCCACCGG                     #CATCTCCGCG   480CCCAGGG CCACCTCGAC GCGGGCGCCA AGAAGGTCAT                     #GTACGACGGC   540AGGACAT CACCATCGTG CTCGGCGTCA ACGACGACAA                     #GCTGGCGAAG   600TCTCCAA CGCGTCGTGC ACCACGAACT GCCTCGGCCC                     #CGCCTACACC   660AGTTCGG CATCGTCAAG GGCCTGNTGA CCACCATCCA                     #CGCCGCCGCG   720TGCAGGA CGGCCCGCAC AAGGATCTGC GCCGGGCCCG                     #GCTGCCCGAG   780CGACCTC CACCGGTGCC GCCAAGGCCA TCGGACTGGT                     #CTCGGTCACC   840TCGACGG CTACGCGCTG CGGGTGCCGA TCCCCACCGG                     #CGCGATGA     898AGCTGGG CAAGTCGGCC ACCGTGGACG AGATCAACGC                     - (2) INFORMATION FOR SEQ ID NO:186:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 268 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:186:                               #Gly Arg Ile Gly Arg Asnly Val Asn Gly Phe                                    #                 15                                                          #Glu Gly Lys Asn Lys Aspsp Ala Gln Lys Ala                                    #             30                                                              #Asp Asn Ala Thr Leu Alaal Asn Asp Leu Thr                                    #         45                                                                  #Arg Leu Pro Tyr Asp Valsp Ser Ile Leu Gly                                    #     60                                                                      #Gly Ser Thr Lys Ile Lyssp Thr Ile Val Val                                    # 80                                                                          #Leu Pro Trp Gly Asp Leulu Gly Pro Ala Ala                                    #                 95                                                          #Ile Phe Thr Lys Arg Aspal Glu Ser Thr Gly                                    #            110                                                              #Lys Lys Val Ile Ile Sereu Asp Ala Gly Ala                                    #        125                                                                  #Val Leu Gly Val Asn Asplu Asp Ile Thr Ile                                    #    140                                                                      #Ser Asn Ala Ser Cys Threr Gln Asn Ile Ile                                    #160                                                                          #Ile Asn Asp Glu Phe Glyro Leu Ala Lys Val                                    #                175                                                          #Ala Tyr Thr Xaa Val Glnaa Thr Thr Ile His                                    #            190                                                              #Arg Arg Ala Arg Ala Alaro His Lys Asp Leu                                    #        205                                                                  #Ala Ala Lys Ala Ile Glyro Thr Ser Thr Gly                                    #    220                                                                      #Asp Gly Tyr Ala Leu Argeu Lys Gly Lys Leu                                    #240                                                                          #Leu Thr Ala Glu Leu Glyly Ser Val Thr Asp                                    #                255                                                          #Ala Meter Ala Thr Val Asp Glu Ile Asn Ala                                    #            265                                                              - (2) INFORMATION FOR SEQ ID NO:187:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 41 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:187:                               #Thr Glu Lys Leu Gly Sereu Ile Asp Val Leu                                    #                 15                                                          #Asn Val Val Asp Thr Ilehr Ala Ala Val Glu                                    #             30                                                              -  Val Ala Ala Val Pro Lys Xaa Val Val                                        #         40                                                                  - (2) INFORMATION FOR SEQ ID NO:188:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 26 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:188:                               #              26  CTSAT YGAYGT                                               - (2) INFORMATION FOR SEQ ID NO:189:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 20 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:189:                               # 20               TTYTC                                                      - (2) INFORMATION FOR SEQ ID NO:190:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 84 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:190:                               #GACTGCGGCA    60TACTCAC TGAGAAGCTG GGCTCGGATT GTCGGCAAGC                     #                84CACAC CATA                                                 - (2) INFORMATION FOR SEQ ID NO:191:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 337 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:191:                               #GACTGCGGCG    60TACTCAC TGAGAAGCTG GGCTCGGATT GTCGGCAAGC                     #CGTCACCATC   120TCGACAC CATCGTGCGC GCCGTGCACA AGGGTGAGAG                     #CAATCCGCGC   180TTTTCGA GCAGCGTCGT CGCGCAGCAC GCGTGGCACG                     #CGGCGCTCAG   240TGAAGGT CAAGCCCACC TCAGTCCCGG CATTCCGTCC                     #GGTCAAGCGC   300TCTCTGG CGCACAGAAG CTTCCGGCCG AGGGTCCGGC                     #     337          AGCAC CGCCCGCAAG GCAGCCA                                   - (2) INFORMATION FOR SEQ ID NO:192:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 111 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:192:                               #Gly Ser Asp Arg Gln Alaeu Thr Glu Lys Leu                                    #                 15                                                          #Ile Val Arg Ala Val Hissn Val Val Asp Thr                                    #             30                                                              #Gly Val Phe Glu Gln Arghr Ile Thr Gly Phe                                    #         45                                                                  #Arg Thr Gly Glu Thr Valal Ala Arg Asn Pro                                    #     60                                                                      #Arg Pro Gly Ala Gln Pheer Val Pro Ala Phe                                    # 80                                                                          #Pro Ala Glu Gly Pro Alaly Ala Gln Lys Leu                                    #                 95                                                          #Ala Arg Lys Ala Alaal Thr Ala Thr Ser Thr                                    #            110                                                              - (2) INFORMATION FOR SEQ ID NO:193:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 1164 base                                                         (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:193:                               #GGTGCGGGCG    60GAGAAGC GCCCGCCCCG GTTCACGGGC GCCTGATCAT                     #GCTGCGCGCC   120GCTTCGG GACGGCCTCA CTGCTGGCCG GCGGGTTCGT                     #GGTGGCGCGC   180CTGCCGC CCTCGGCGCG ACTCCGGGCG AGGTCGCGCC                     #GGGCATCACG   240ACCGCGA CGGCAAGTTC GTCAACCTGG AGCCCCCGTC                     #ATCCCAGGGC   300TGCAGCG GATGCTGTTG CGCGATCTGG CCAACGCCGC                     #TCCCGCGCCG   360CGATCCC GCTGGCCGAG CCGCCGAAGG GGGATCCCAC                     #CTACCGCGTG   420GGTACGG CCATTCCAGC GTGCTGATCG AGGTCGACGG                     #ACCGCAGCGC   480TGTGGAG CAACAGATGT TCGCCCTCAC GGGCGGTCGG                     #GGTGATCAGC   540CGGTGCC GCTGGAGGCG CTTCCCGCCG TGGACGCGGT                     #CACCCAGCGG   600ACCACCT CGACATCGAC ACCATCGTCG CGTTGGCGCA                     #CGTCCCCGAG   660TGCCGTT GGGCATCGGC GCACACCTGC GCAAGTGGGG                     #GACGCTGGTC   720AGTTGGA CTGGCACGAA GCCCACCGCA TAGACGACCT                     #GCTGTGGGCG   780GGCACTT CTCCGGACGG TTGTTCTCCC GCGACTCGAC                     #CGGATACACG   840CCGGCTC GTCGCACAAG GCGTTCTTCG GTGGCGACAC                     #GCTGCCGATC   900AGATCGG CGACGAGTAC GGTCCGTTCG ATCTGACCCT                     #GGTGCGCGCC   960CCGCGTT CGCCGACATC CACATGAACC CCGAGGAGGC                     #GGCGACATTC  1020CCGAGGT GGACAACAGC CTGATGGTGC CCATCCACTG                     #TGCCGACGCC  1080ATCCGTG GTCCGAGCCC GCCGAACGCC TGCTGACCGC                     #GTCGACGTTC  1140TGACCGT GCCGATTCCC GGTCAGCGGG TGGACCCGGA                     #              1164TTCTG AACC                                                 - (2) INFORMATION FOR SEQ ID NO:194:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 370 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:194:                               #Gly Thr Ala Ser Leu Leueu Arg Tyr Gly Phe                                    #                 15                                                          #Gly Thr Pro Ala Ala Leueu Arg Ala Leu Gln                                    #             30                                                              #Ala Arg Arg Ser Pro Asnlu Val Ala Pro Val                                    #         45                                                                  #Pro Pro Ser Gly Ile Thrhe Val Asn Leu Glu                                    #     60                                                                      #Arg Asp Leu Ala Asn Alaln Arg Met Leu Leu                                    # 80                                                                          #Pro Leu Ala Glu Pro Proro Pro Gly Pro Ile                                    #                 95                                                          #Ala Ser Trp Tyr Gly Hisro Ala Pro Ala Ala                                    #            110                                                              #Arg Val Leu Ala Asp Prolu Val Asp Gly Tyr                                    #        125                                                                  #Ala Val Gly Pro Gln Argys Ser Pro Ser Arg                                    #    140                                                                      #Leu Pro Ala Val Asp Alaal Pro Leu Glu Ala                                    #160                                                                          #Leu Asp Ile Asp Thr Ilesp His Tyr Asp His                                    #                175                                                          #Phe Val Val Pro Leu Glyhr Gln Arg Ala Pro                                    #            190                                                              #Pro Glu Ala Arg Ile Valrg Lys Trp Gly Val                                    #        205                                                                  #Asp Asp Leu Thr Leu Vallu Ala His Arg Ile                                    #    220                                                                      #Leu Phe Ser Arg Asp Seris Phe Ser Gly Arg                                    #240                                                                          #Ser Ser His Lys Ala Pherp Val Val Thr Gly                                    #                255                                                          #Phe Ala Glu Ile Gly Asply Tyr Thr Lys Ser                                    #            270                                                              #Pro Ile Gly Ala Tyr Hissp Leu Thr Leu Leu                                    #        285                                                                  #Glu Glu Ala Val Arg Alale His Met Asn Pro                                    #    300                                                                      #Leu Met Val Pro Ile Hislu Val Asp Asn Ser                                    #320                                                                          #Trp Ser Glu Pro Ala Glueu Ala Pro His Pro                                    #                335                                                          #Val Arg Leu Thr Val Prola Asp Ala Glu Arg                                    #            350                                                              #Thr Phe Asp Pro Trp Trpal Asp Pro Glu Ser                                    #        365                                                                  -  Arg Phe                                                                         370                                                                 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I claim:
 1. A method for enhancing a non-specific immune response to anantigen comprising administering delipidated and deglycolipidated M.vaccae cells.
 2. A composition comprising delipidated anddeglycolipidated M. vaccae cells.
 3. A method for inducing an immuneresponse in a patient comprising administering a composition accordingto claim
 2. 4. The composition of claim 2, wherein the delipidated anddeglycolipidated M. vaccae cells comprise less than 10% by weight oflipids.
 5. The composition of claim 2, wherein the delipidated anddeglycolipidated M. vaccae cells comprise more than 33% by weight ofamino acids.